PIP implants - current knowledge and literature review

INTRODUCTION

Non-compliance with the production process during the production of PIP implants revived an extensive debate regarding regulation and control mechanisms during production of breast implants and other medical devices, but reopened also the question of health safety of breast implants in general. Despite breast implants are classified in EU and USA as very risky medical device (class III) and they are therefore subject to more strict rules, regulation mechanisms are completely different.

In the US, the manufacturer must demonstrate safety and efficacy of implants by extensive and long term clinical studies in order to obtain approval from Food and Drug Administration (FDA). FDA is blamed, however, that it was not sufficiently controlling that performed studies were of good quality and were correctly evaluated and interpreted. In relation with the PIP implants is the agency blamed that it was not able to prevent illegal sale of PIP implants several years after they were prohibited in the US. In the European Union (EU) the manufacturer must obtain CE (Conformité Européenne) certification and for that the manufacturer must only demonstrate that the manufacturing process is in compliance with prescribed directives and norms. Competent authorities must control compliance with these norms. According to the current regulations in force, the product may be distributed and sold in all countries of the European Union, if it obtains CE certification in any of the EU countries ^1,2. The medical safety of breast implants is controlled by EQUAM (European Committee on Quality Assurance & Medical Devices in Plastic Surgery), which issues opinion regarding safety of implants in general, but it has no right related to the control of the manufacturing process of the implants, etc.^3–5.

Although the question of general safety of breast implants was already concluded mainly based on the report of the IOM (Institute of Medicine) in the US in 1999, it reappeared again with regards to the new risk factor of Anaplastic Large Cell Lymphoma – ALCL)^6,7. This very rare lymphoma repeatedly occurred in the patients with breast implants. There were so far 130 cases of this disease in women with breast implants, from which four had a PIP implant. The disease had a fatal end in one patient with ALCL and PIP implant. The problem was immediately investigated by FDA with the conclusion that according to the current knowledge there is a minimal, but still a higher risk to develop ALCL in women with breast implants, however use of breast implants in accordance with instructions is safe ^4,8.

HISTORY OF PIP IMPLANTS

The company Poly Implant Prothéses (PIP) obtained approval for production and distribution of breast implants in 1997. PIP implants were produced in the current design since 2001 as smooth and textured. The manufacture process, which obtained CE certification, declared quality at the level of third generation implants. The company obtained the certification via German authorized body TUV Rheinland. However, the implants became characteristic soon of high incidence of ruptures and leakage and behaved rather as implants of second generation^3,8.

It has been estimated that the company produced approx. 600,000 implants, in which it did not follow the certified manufacture process and materials. From that follows that there is around 300,000 women from 65 countries of the world who might have faulty PIP implants. Most of them come form the countries of South America. Between the years 2001–2009, there were approx. 80,000 of these implants sold in the United Kingdom and around 60,000 in France, which represents approx. 40,000 and 30,000 women, respectively. In the United States, however, with regards to more strict regulations, there were only few of these implants used^3,5,8.

PIP implants were manufactured by the French company Poly Implant Prothéses, later also under the names M-Implants, Rofil Implants and TiBreeze. Since 2006 there were references from aesthetic surgeons that these implants have a higher risk of rupture and the British Medicines and Healthcare Products Regulatory Agency – MHRA warned the manufacturer about this and also the appropriate control authority. Nevertheless, the warning was put aside with the explanation that the rise of rupture rate is a natural feature due to higher distribution of the product and a more precise reporting of complications. MRHA notified again in 2009 when the UK Health Department published a research, which compared the incidence of PIP implants ruptures of 15–30% with the incidence of 10–14% in implants of other brands. In March 2010 the French agency Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS) found that during the production of PIP implants was not used the approved medicinal grade silicon gel, but an industrial gel and production and distribution of implants was prohibited. MHRA responded on 31^st of March 2010 by the issue of Medical Device Alert-MDA/2010/025 in which it prohibited the usage of PIP implants in the UK^3,5,8,9.

In the United States were the PIP implants excluded from legal use several years before that due to the doubts about their safety. As early as in 2000, the FDA scientific board stated that published documents of PIP Company are not valid and FDA prohibited usage of PIP Implants in the USA. Based on this decision, the PIP Company requested the possibility to perform studies in the USA. FDA inspection therefore performed check of manufacture process in the production facility of PIP, where it found eleven significant deviations from certified production process and did not recommend even any studies with PIP implants in the country^{3,5,8,10–12}.

THE PIP ISSUE

Uncovering of production and material deviations related to PIP implants resulted in extensive investigation process in the manufacturer and responsible health authorities in individual countries in which PIP implants were distributed, and they had to take an adequate stand and declare measures for doctors and patients. This all took place under a great pressure of media.

In December 2011 and January 2012 French medical authorities published recommendations for women with PIP implants. Each woman, who had PIP implants, should visit her doctor and if there was a suspicion or demonstrated rupture of the implant, the implant should have been immediately removed. PIP implants should however be preventively removed in all women also in case that they were all right and in women who had no clinical problems and finally, early regular checks were needed in women who refused removal of the implant^13,14.

On the other hand, MHRA, based on its studies, declared that in women with PIP implants was not demonstrated any significant health risk and it is not needed to remove the implants routinely^15–18.

In December 2011 experts from Great Britain, France, Italy, Austria and Denmark initiated a conference concerning the risks of PIP implants and determination of further procedure. After this conference the health authorities in France, Netherlands, Germany, Czech Republic and Venezuela issued a statement that PIP implants should be preventively removed in women.

In January 2012 the Medical Director of the National Health Trust UK made a definite statement based on a thorough analysis by a group of specialists. The conclusion of the analysis stated that there is no demonstrated health risk of technical silicon that is used in PIP implants (genotoxicity, cytotoxicity, cancerogenity, …), however these implants have a greater tendency of failure and local symptoms then implants of other brands¹⁹. Therefore, MHRA in Great Britain, in contrast to the decision in other states, declared that implants need not to be preventively removed. This resulted in great wave of protests of the public and MHRA soon issued a corrective statement that the National Health System – NHS will pay for removal and exchange of PIP implants to women in whom the primary procedure was paid by the NHS and the doctor and the patient declare that the exchange is the best solution for the patient. Simultaneously was the same procedure offered also by the private clinics that performed aesthetic augmentation of the breasts^20–23.

Expert panel of Australian Board for Therapeutic Goods Administration (TGA) repeatedly declared that based on current knowledge, there is no need for routine removal of PIP implants in case that they are not ruptured, however women with these implants should undergo complex examination including MRI²⁴.

The International Confederation of Plastic, Recon-structive and Aesthetic Surgery Societies also joined the discussion in early 2012 and stated that: “There is no further space for discussion, our obligation is to recommend removal of PIP implants”²⁵. However, for the whole duration of this scandal, each country worldwide or within Europe did not agree upon a uniform procedure.

QUALITY OF PIP IMPLANTS

In 2010, French health authorities performed investigations and tests of PIP implants with regards to the chemical composition of silicon, quality of silicon capsule and toxicological point of view. Implants were produced with three surface finishes, as smooth, microtextured and textured. In 2007 was eliminated barrier layer from the capsule. A detailed analysis demonstrated that during the production there was no certified medicinal gel used for a long time but an industrial gel of lower purity with high content of small particles and with lower stability. Exact type of gel cannot be found in literature; however the company states usage of PIP1 gel until 2008 and then PIP2 gel. Media report usage of three various gels including Baysilone and Silopren (Bayer AG, Germany) and Rhodorsil (Bluestar Silicones, France). Some of these gels are declared by the manufacturers as possibly suitable for medical use, but without further specifications ^8,26,27. Australian Therapeutic Goods Administration (TGA) confirmed that gel in PIP implants contains significant quantity of small cyclic siloxanes: D4 (0–261 ppm), D5 (0–710 ppm) and D6 (0–1005 ppm), which are not present in the implants of other brands ²⁴.

For the testing of mechanical properties of implants were used 12 implants, from which 6 were smooth and 6 were textured. Implants with smooth surface complied with more parameters than the textured implants. Textured implants did not comply with the norm for elongation at break and ruptured earlier, both types of implants did not comply with the norm for mechanical elongation tear test. Cytotoxic “in vitro” test did not demonstrate cytotoxicity of gel in the implants. Genotoxic testing ruled out genotoxic effects of gel; development of mutations and gene aberrations on bacteria and lymphocytes was not demonstrated. However, intradermal irritation test on rabbits demonstrated that silicon gel in PIP implants has a certain irritation potential, which did not manifest in gels of other implants ³. Irritation potential of silicon gel used during production of PIP implants was not confirmed by other studies ⁸.

SCIENTIFIC VERIFICATION OF PIP IMPLANTS SAFETY

European Union shortly appointed an international group called Scientific Committee on Emerging and Newly Identified Health Risks – SCENIHR to deal with this issue. The commission performed an extensive literature review regarding breast implants, mainly those dealing with PIP implants since 1998. There were more than 1,000 articles identified that dealt with complications of breast implants, their medical risks such as carcinomas, connective tissue disorders, neurological diseases, toxicological aspects, adverse effects of implantation and explantation, etc. Another branch reviewed in detail the articles regarding the production process of implants, composition of each part of the implants, the extent of silicon impurity, etc.³. The commission issued a report on 1^st February 2012 with the conclusion that PIP implants could be significantly different with regards to the quality of processing and used materials and therefore could demonstrate significantly different properties and behaviour after implantation. Published cases suggest that PIP implants have a higher risk of rupture within the early postoperative period and in case of rupture have a greater risk of local symptoms and higher risk of inflammatory lymph nodes. Limited data therefore suggest that women with PIP implants have a higher risk of medical problems than women with implants from another manufacturer. To confirm these suspicions it is however necessary to collect a maximal amount of data about physical, chemical and biological properties of PIP implants and implants of other brands. In September 2013, SCENIHR updated the conclusion from 2012 saying that there is no clear medical, toxicological or other data to explain preventive removal of undamaged PIP implants¹². Another detailed update from May 2014 confirms that despite repeated references about increased rupture rate of PIP implants it is not possible to demonstrate this clearly, since the ruptures of PIP implants as well as other implants are not sufficiently documented. In case of PIP implants there is however a very high variability in quality and thickness of silicon shell of the implant between various implants as well as in one particular implant, which indicates poor control of the production process and its variability. This could explain high incidence of ruptures in some studies. In some cases is the rupture or leakage of implants associated with inflammatory reaction, in some cases not, and the reason of such difference in each patient is not clear. Rupture of the implant or inflammatory reaction is not associated with higher risk of breast cancer or ALCL. Implants contain more specific small cyclic siloxanes (D4, D5, D6) then implants of other brands, they are however present also in women without breast implants and do not show any toxic or irritation properties in standard tests. There were no other foreign organic or inorganic substances demonstrated in the implants, not even in trace quantities. The commission concludes that there is no valid data to support preventive removal of undamaged PIP implants. It is however suitable to consider removal in women who show significant psychological stress to have these implants in their body⁸.

RISK OF COMPLICATIONS OF SILICON BREAST IMPLANTS IN GENERAL

To find out whether PIP implants have a higher risk of ruptures and other complications, it is naturally needed to know the level of risk in implants of other brands. In the world market there is a great number of implants of various brands and manufacturers from various countries. Nevertheless, literary resources, which dealt specifically with complications in individual implant brands, are virtually missing and most references deal with complications of implants in general. There is however a valuable FDA study, which deals with safety of Allergan and Mentor implants and it is related to extensive studies, which were needed to grant approval of FDA for distribution and use of silicon filled implants of these manufacturers for aesthetic goals in the United States. The study was first introduced in 2006 and was updated in 2012.

The report from 2012 evaluates the results after ten years from implantation of Allergan implants and after 8 years from implantation of Mentor implants. Evaluated studies had variably large files and they were performed totally on 39,390 patients with Allergan implants and 41,900 with Mentor implants.

The rate of Allergan implant rupture risk was 10.1% in primary augmentation, 6.3% in revision augmentation, 27.2% in primary reconstruction and 6.7% in revision reconstruction. The rate of Mentor implant ruptures in the same categories was 13.6%, 15.5%, 14.0% and 21.3%, respectively. Connective tissue disorder occurred during the aforementioned period in 6 patients with Allergan implants and in 28 patients with Mentor implants⁴. The following complications were reported in patients with Allergan implants: breast pain in 6.8–11.7%, capsular contracture Baker 3–4 in 6.7–27.5%, infection in 0–3.2% and seroma in 1.8–6.7%. In the recipients of Mentor implants were reported the following complications: breast pain in 2.5–5.2%, capsular contracture Baker 3–4 in 10.9–24.1%, infection in 0–6.2% and seroma in 1.1–4.8%. The most frequent reason for implant exchange in both brands was the request of the patients for a change of size and type of implant and also capsular contracture, infection and implant rupture. Complications in both types of implants occurred more frequently during reconstruction of breasts after mastectomy, and then in aesthetic augmentations⁴.

The results of this FDA report evaluating valid studies in more than 80,000 implant holders of the two manufacturers could basically serve as a reference data for evaluation of implants of other brands including PIP implants.

SCIENTIFIC PUBLICATIONS ON PIP IMPLANTS

At the time when the issue with the PIP implants was revealed, there were no studies to investigate these implants separately. Confirmation of non-compliance with the certified manufacture process and use of industrial silicon resulted in recommendation of national and international societies about collection of maximal quantity of information regarding behaviour of these implants and shortly started to occur case reports and cohort studies describing the occurrence of ruptures, complications and complaints or individual severe complications.

As early as in 2011 was published a case of a patient with a rupture of PIP implants with axillary lymphadenopathy and with multiple foci of granulomatous giant cell inflammation in the skin of the limbs, which only gradually subsided after removal of implants and capsulectomy²⁸. Another case report describes unilateral chronic abacterial inflammation of areolomamilary complex in a PIP implant, which quickly subsided after removal of the implant and capsulectomy ²⁹. Similar case reports were reported also later³⁰. Limited number of only six patients, who attended for medical examination due to complaints, is published by Malata. The prostheses were implanted for 2–11 years. All women had some type of a problem – chest and axillary discomfort, swelling of the breast or palpable granulomas in axilla. In five women was ruptured one implant, in one were ruptured both implants, purulent discharge around implant was present in five women, thicker capsule was also present in five women. Based on the experience, the author proposes a complex algorithm of care for women with PIP implants ³¹. One of the articles reports interesting data regarding silicon lymphadenopathy. The author reports a group of 14 patients in his practice in whom this complication was clinically demonstrated. The patients were divided to two time periods. In the first group – until the year 2000, there were 4 patients who had various types of implants, age of implants was 12–34 years. In the second group – period from 2006–2009, there were ten patients and all had PIP implants, age of implants was 2–6 years. The weak point of this reference is the fact that the file includes selectively patients who attended for examination due to the complaints or in whom there was pathology diagnosed during screening³².

Carillon in 2012 found three ruptured implants in eight patients after removal of PIP implants; the rupture was symptomatic in two of them³³. Other publications report 11.9% of patients with a rupture of implants that was verified surgically on a file of 453 patients. The duration of implantation was 7–12 years. In this file, 10.4% of women refused any intervention including preventive examination, because they had no complaints³⁴. Chummun in his article reports a group of 44 patients with totally 78 PIP implants with duration of implantation of 5–13 years. In his group there were 17 (21.8%) implants with a rupture, from which 15 were completely disintegrated. Most patients in the aforementioned group (70.5%) had no problems; symptomatic patients had most often capsular contracture and axillary lymphadenopathy³⁵. Another article reports a cohort of 455 patients from one clinical site with totally 828 PIP implants. Time from implantation to removal was 2–11 years. Rupture was confirmed in 7.7% of patients, presence of silicon in capsule was demonstrated in 26% and inflammatory reaction of the capsule in 13% of implants. In 23.5% of implants was demonstrated capsular contracture Baker 2–3, grade 4 was not present and in 2.9% of implants was demonstrated swelling of the breast gland. Fluid around the implants was demonstrated in 5.2% of cases³⁶. Publications from the United Kingdom describe a group of 338 patients with 676 PIP implants who underwent surgery by one surgeon. The incidence of rupture was totally 21.3%, there was significantly higher number of ruptured implants that were implanted after the year 2003 (24.1%) then before this year (11.3%). In 29.4% of patients there was spread of silicon demonstrated in the axillary lymph nodes. Interesting finding of the authors is a significantly higher number of ruptures in implants placed below the muscle (26.1%) then below the gland^14,8,37. Maijers confirms rupture of PIP implants in his group of patients in 21% of cases³⁸. Based on three larger studies of patients with PIP implants, Berry warns about the fact that whereas before the year 2000 the PIP implants had approximately the same life time than implants of other brands, after 2005 the life time shortened to almost half (the time to rupture from 10.5 to 5.8 years). The author also notes how much media influence the interest of patients about dealing with the problems with PIP implants. After maximal media attention about PIP implants in December 2012, the author was contacted during the months of January to March 2013 by almost 90% of patients, whereas during the next period the interest rapidly declined^{39, 40}. Another study from the United Kingdom demonstrates that in 143 patients of comparable age, comparable size and age of implants was not significantly different in the incidence of capsular contracture between PIP implants and implants of other brands. Ruptures of PIP implants were however significantly more frequent (27.7% versus 7.6%) (41).

Attention was paid also to materials used for production of PIP implants. Beretta et al. published an article where they compared chemical properties of highly cohesive gel of PIP implants after explantation, gel from the new McGhan 410 MX implant and technical non-cohesive silicon. The results have shown that in comparison with the new McGhan implants, the PIP lost part of the bonds needed for high cohesivity gel, there was high level of lipophilic particles such as squalene, cholesterol and its precursors, which penetrated from the breast gland and the implant capsule had insufficient barrier layer. The weak point of the study is that only two implants were examined ⁴². Another article dealt with mechanical properties of silicon capsule of breast PIP implants in comparison with implants of other brands. There were 14 used PIP implants examined and 4 implants of other brands that were explanted in patients at Royal Free Hospital in London and the results were compared with new PIP implants. The study demonstrated significant differences. The capsule of PIP implants, new and explanted ones, was more susceptible to rupture, it was more sensitive to degradation processes that influence the implant in vivo and implants were significantly heterogeneous in its properties⁴³.

Since there was a high pressure of the public regarding general exchange of PIP implants and health authorities in some countries recommended it, there was also a debate about medical risks of removing implants in general, undamaged and also ruptured ones. The goal of this discussion was to evaluate the risk of explantation, and to find out whether this risk exceeds the benefits of the procedure. The risk of explantation includes the risk of anaesthesia and risk of actual operation. As far as concerns anaesthesia, it should be considered that most women, who have PIP implants, are younger and healthy women, they underwent general anaesthesia during implantation and therefore the risk of anaesthesia is expectable. In the modern anaesthesia is the risk of serious complications very low, it is commonly accepted as a part of breast augmentation complications or in women with unsatisfactory result and independently on the implant manufacturer. Therefore this risk plays no significant role. It was estimated in a study that the risk of death during general anaesthesia in healthy individuals has an incidence of 1:250,000⁴⁴. General anaesthesia may be however complicated with anaphylaxis or aspiration and the risk of these complications is estimated to 1:6000–7000; it is however lower in healthy people⁴⁵. The risk of the surgical procedure in simple explantation is comparable with other procedures on the breast and in general apply the same rules as for the risk of anaesthesia. In case of PIP implants should be however considered a bit higher risk. With regards to the defectiveness of implants there is a higher probability of gel leakage and local irritation and inflammatory reactions. Therefore it is suitable to remove the implant and also the capsule, so that the effect of explantation was the highest. Removal of the implant with capsulectomy is a procedure that is more demanding and longer, there is a higher risk of bleeding, longer hospitalization is usually required and for the patient means greater invasivity and pain. In case of larger lymph nodes with clinical symptoms, it is suitable to remove also these with additional risk for the patient³.

The advocates of general removal of all PIP implants logically use two main arguments. First argument is that implants are produced from materials, which do not fulfil the norms for medically harmless medical device and represent a potential medical risk for the patient despite there were no significant negative effects of technical silicon demonstrated. The second argument is that from the medical and financial point of view, it is clearly more advantageous to remove the intact implant, which is relatively simple and less risky procedure than removal of ruptured implant or even an implant already with local and distant complications⁴⁶.

Increase in the number of examinations in women with breast implants after recommendation of the national agencies resulted also in publishing of articles with revisions and updates of findings from ultrasound examinations of the breast with similar description of images of implant ruptures and possible variations in the findings⁴⁷ and comparison of ultrasound, mammography and MRI findings of breast implant ruptures⁴⁸. These and other studies again confirmed MRI as the most reliable method for examination of implant ruptures⁸.

Nevertheless, there are also publications, which inform about the presence of inappropriate publicity up to sensational nature of PIP implants and possibility of inadequate and non-scientific decision or statement under pressure of media and opinion of public. Freshwater in his article compares the situation with PIP implants with the situation when FDA prohibited the use of silicon filled implants in the USA for aesthetic surgery. This prohibition was due to the pressure of media and public and was based on insufficient scientific basis. Prohibition was then cancelled after further investigation; in the meantime it however resulted in a great number of lawsuits, bankruptcy of companies and mainly in panic and fear in thousands of women. This is similar situation as in PIP implants. The author warns that all objections against safety of PIP implants are based on presumptions or sporadic cases. Even the statement that PIP implants rupture more frequently is slightly doubtful. How is it possible to demonstrate more frequent ruptures, when it is not possible to find what quantity of these implants was actually implanted to women. The author also has the same objections against possible toxicity of used gel, etc.⁴⁹.

PRECAUTIONS FOR PREVENTION OF REPEATED BREACH OF IMPLANT PRODUCTION PROCESS

Solution of problems with PIP implants resulted in Europe, apart from questions how to solve the medical risks of these implants, also to discussion of medical and legislation specialists and authorities regarding more strict conditions to market new implants. In the year 2012, European commission suggested more strict regulatory mechanisms and provisions of the commission, which would control and review the evaluation and granting of CE certification to medical devices, which may now be granted by more than 80 national agencies^50–53.

CONCLUSION

The founder and owner of Poly Implant Prothéses Jean-Claude Mas was sentenced to 4 years in jail in December 2013 and a fine of 75,000 Euro. He lodged an appeal against the sentence. There are currently two judicial proceedings in association with the case of PIP implants. The first lawsuit deals with inadvertent harm and killing and the other concerns tracking of the supposed millions of profit of the company achieved by fraud during the production process. In the same time the German authority TÜV, which granted the PIP Company the CE certification, was sentenced by the court in Toulon to a financial compensation of 5.8 million Euros to six companies, which distributed PIP implants to the whole world⁵⁴.

The scandal of breast implants manufactured by PIP Company has shown that virtually in no medical device the doctor can guarantee 100% medical safety. This harmlessness is stipulated by the rules and regulations, however it depends on two factors, which the doctor, or medical facility cannot influence by any way. The first factor is the actual manufacturer, who must observe the production process according to prescribed norms as well as the use of certified materials. The second factor is adequate primary and subsequent control activity of responsible authority, which granted the certification to the manufacturer of the medical devices.

The PIP case is not a scandal of breast implants. It is a scandal of a group of fraudulent businessmen. In PIP implants there was a purpose-built and intentional violation of the manufacture process by the manufacturer and change of used materials for cheaper and non-certified materials. Subsequently there was a fatal failure of authorities, who granted the certificate to the manufacturer and for several years did not notice the change of manufacture process and change of materials. Defectiveness of the implants was confirmed only after repeated notifications of the doctor to non-standard behaviour of these implants. Doctors were paradoxically significantly affected by this scandal financially and legally.

Corresponding Author:

Martin Molitor, M.D.

Department of Plastic Surgery, Hospital na Bulovce and 1^st Faculty of Medicine

Charles University, Budínova 2

180 81 Prague 8, Czech Republic

E-mail: martin.molitor@bulovka.cz