Pelvic organ prolapse surgical management in Portugal and FDA safety communication impact on vaginal mesh

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2013/2014

Miguel José da Quinta e Costa de Mascarenhas Saraiva

Pelvic organ prolapse surgical management in Portugal and

FDA safety communication impact on vaginal mesh

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Mestrado Integrado em Medicina

Área: Obstetrícia e Ginecologia

Trabalho efetuado sob a Orientação de:

Professora Doutora Amélia Assunção Beira de Ricon Ferraz

E sob a Coorientação de:

Dra. Paula Cristina da Silva Nogueira

Trabalho organizado de acordo com as normas da revista:

International Urogynecology Journal

Miguel José da Quinta e Costa de Mascarenhas Saraiva

Pelvic organ prolapse surgical management in Portugal and

FDA safety communication impact on vaginal mesh

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Projeto de Opção do 6º ano - DECLARAÇÃO DE INTEGRIDADE

Eu, Miguel José da Quinta e Costa de Mascarenhas Saraiva, abaixo assinado, nº mecanográfico 200707261, estudante do 6º ano do Ciclo de Estudos Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto, declaro ter atuado com absoluta integridade na elaboração deste projeto de opção.

Neste sentido, confirmo que NÃO incorri em plágio (ato pelo qual um indivíduo, mesmo por omissão, assume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou redigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica.

Faculdade de Medicina da Universidade do Porto, 06/03/2014

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Projecto de Opção do 6º ano – DECLARAÇÃO DE REPRODUÇÃO

NOME

Miguel José da Quinta e Costa de Mascarenhas Saraiva

CARTÃO DE CIDADÃO OU PASSAPORTE (se estrangeiro) E-MAIL TELEFONE OU TELEMÓVEL

13505656 miguelmascarenhassaraiva@gmail.com 910369496

NÚMERO DE ESTUDANTE DATA DE CONCLUSÃO

200707261 2014

DESIGNAÇÃO DA ÁREA DO PROJECTO

Obstetrícia e Ginecologia

TÍTULO DISSERTAÇÃO/MONOGRAFIA (riscar o que não interessa)

Pelvic organ prolapse surgical management in Portugal and FDA safety communication impact on vaginal mesh

ORIENTADOR

Professora Doutora Amélia Assunção Beira de Ricon Ferraz

COORIENTADOR (se aplicável)

Dra. Paula Cristina da Silva Nogueira

É autorizada a reprodução integral desta Dissertação/Monografia (riscar o que não interessa) para efeitos de investigação e de divulgação pedagógica, em programas e projectos coordenados pela FMUP.

Faculdade de Medicina da Universidade do Porto, 06/03/2014 Assinatura conforme cartão de identificação:

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À Minha Família

Aos Meus Mestres

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1

Title: Pelvic organ prolapse surgical management in Portugal and FDA

safety communication impact on vaginal mesh

Author Details:

Teresa Mascarenhas, Department of Gynecology and Obstetrics, Hospital S. João, Faculty of Medicine of Porto University, Porto, Portugal

Miguel Mascarenhas-Saraiva Jr., Faculty of Medicine of Porto University, Porto, Portugal

Amélia Ricon-Ferraz, Department of Social Sciences and Health, Faculty of Medicine of Porto University, Porto, Portugal

Paula Nogueira, Department of Obstetrics and Gynecology, Hospital S. João, Porto, Portugal

Fernando Lopes, Centre for Research in Health Technologies and Information Systems (CINTESIS), Faculty of Medicine of Porto University, Porto, Portugal

Alberto Freitas, Centre for Research in Health Technologies and Information Systems (CINTESIS), Faculty of Medicine of Porto University, Porto, Portugal

Corresponding Author:

Teresa Mascarenhas

Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina da Universidade do Porto. Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal

Telephone: +351 913 231 207 E-mail: tqc@sapo.pt

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2 Each authors' contribution to the Manuscript:

Teresa Mascarenhas: Project development, Data collection/management, Data analysis, Manuscript writing/editing

Miguel Mascarenhas-Saraiva Jr.: Project development, Data collection/management, Data analysis, Manuscript writing/editing

Amélia Ricon-Ferraz: Project development, Data management, Data analysis, Manuscript editing

Paula Nogueira: Data management, Manuscript editing

Fernando Lopes: Data collection/management, Manuscript editing Alberto Freitas: Data analysis/statistical analysis, Manuscript editing

Ethical/Institutional Review Board Approval:

This study is not subject to approval by the Ethical/Institutional Review Board, since data was retrieved from a national database (the Portuguese National Medical Registry (clinical-administrative data)) from which patient identifying information is not available to the research team (all patient identifying information is encrypted).

Word counts:

 Body (introduction, methods, results, discussion): 3495 words (max=4000).

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ABSTRACT AND KEYWORDS

Introduction and hypothesis: Pelvic organ prolapse (POP) surgery is an

increasingly important aspect of gynecological practice. This study aims to characterize the evolution of POP surgical procedures conducted in Portugal in the last decade and the impact of FDA 2011 safety communication on mesh POP surgeries.

Methods: Trends in surgical management of POP were assessed using the

Portuguese National Medical Registry. We considered all records of women with diagnosis of genital prolapse from January 1, 2000 to December 31, 2012. Additionally, we also conducted a survey among members of the Portuguese Society of

Urogynecology to evaluate current practices on surgical management of POP. Results: From 2000 to 2012, 46,819 diagnoses of genital prolapse were

registered, with a 105% increase during the study period (2,368 in 2000 to 4,941 in 2012). POP mesh surgery represented only 6% of total prolapse diagnoses, but mesh use greatly increased up to 2011, when only a slight increase was registered. Among gynecologists who responded to the questionnaire, there was considerable variability on the procedures of choice to treat POP. 57% of respondents performed vaginal mesh POP surgery, but only 27% of those actually reported having changed their practice after FDA 2011 safety communication.

Conclusions: POP surgical procedures conducted in Portugal greatly increased

during the last decade. The use of surgical meshes is still limited, but despite FDA safety communication it has increased over the years, with a slight increase in 2012 that portraits the need for further analyses in the coming years.

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4

BRIEF SUMMARY

Pelvic organ prolapse surgeries conducted in Portugal greatly increased during the last decade, but mesh use still limited. FDA communication had limited impact in Portugal.

ABBREVIATIONS

FDA Food and Drug Administration

ICD-9-CM International Classification of Diseases, 9th Revision, Clinical Modification IUGA International Urogynecological Association

POP Pelvic organ prolapse

PSUG Portuguese Society of Urogynecology SPG Portuguese Society of Gynecology

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INTRODUCTION

Pelvic organ prolapse (POP) is a fairly common medical condition worldwide. It affects approximately 40% of women older than 50 years, of which only 25% are symptomatic [1]. The estimated lifetime risk of undergoing POP surgery is 19% [2], which is approximately the double of risk reported in 1990; this increase is perceived as a consequence of population aging and greater awareness of this condition.

Prolapse surgery is an increasingly important aspect of gynecological practice [3]. Over the years, surgical treatment of POP has greatly evolved, and now a variety of surgical techniques are available, but there is not yet definitive evidence on which techniques present the best treatment outcomes [4]. Therefore, the choice of the surgical technique to employ is mostly based on personal experience and training of the surgeon, rather than systematically collected data on the different techniques.

Historically, surgeons relied on patients native tissues to perform repairs, such as anterior and/or posterior colporrhaphy and apical suspensions [5]. However, high recurrence rates were observed, probably due to poor tissue quality [6]. This led to introduction of surgical meshes, which replaced supportive tissue [7]. These surgical meshes were widely used for transvaginal POP repair over the last decade, but their application remains controversial [8]. In 2008, the US Food and Drug Administration (FDA) issued a public health notification raising some doubts about the safety of surgical meshes for transvaginal POP surgery [9]. Still, at this point the FDA concluded that serious adverse events were rare [9]. However, in 2011, the FDA published an updated communication, which included a literature review [10]. This time, the conclusion was that adverse events associated with mesh use are not rare and that there is no definitive evidence that mesh use improves clinical outcomes in comparison with traditional non-mesh repair [10]. This led to a reappraisal of the role of transvaginal mesh in POP surgery both within the US and other countries, with the ultimate goal of maximizing patient outcomes and safety [4,5,8,11,12].

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6 This study aims to characterize the evolution of POP surgical procedures

conducted in Portugal in the past decade (2000–2012) and to evaluate the current practices on POP surgery. Furthermore, the study also aims to assess the general impact of FDA 2011 safety communication on mesh POP surgeries, in particular the impact among Portuguese gynecologists with special interest in urogynecology.

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METHODS

National medical registry

Trends in the surgical management of POP were assessed using data from the Portuguese National Medical Registry (clinical-administrative data), which is managed by the Central Administration of the National Health System. This registry contains information on diagnoses and procedures performed in acute care public hospitals in Portugal, as recorded at patient discharge. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding of both diagnoses and surgical procedures is done by trained coders. Additionally, coding is subjected to regular quality control audits [13].

We considered all records of women with a principal (primary) or secondary diagnosis of genital prolapse, ICD-9-CM code 618.xx, with discharge date from January 1, 2000 to December 31, 2012. Surgical procedures associated these ICD-9-CM code 618.xx diagnoses were also assessed.

Codes for the diagnosis of prolapse included the following: 618.0 prolapse of vaginal walls without mention of uterine prolapse; 618.1 uterine prolapse without mention of vaginal wall prolapse; 618.2 uterovaginal prolapse, incomplete; 618.3 uterovaginal prolapse, complete; 618.4 uterovaginal prolapse, unspecified; 618.5 prolapse of vaginal vault after hysterectomy; 618.6 vaginal enterocele, congenital or acquired; 618.7 old laceration of muscles of pelvic floor; 618.8 other specified genital prolapse; and 618.9 unspecified genital prolapse. Surgical procedures performed in association with the diagnosis of prolapse and categorized by ICD-9-CM code were grouped by prolapse compartment: anterior/posterior and apical. Concomitant

hysterectomy and concomitant incontinence procedures, as well as other procedures, were also grouped, as shown in Table 1. It is noteworthy that ICD-9-CM codes for prolapse repair with graft or prosthesis were only introduced in October 2007 [14], and implementation of new codes is not immediate in some hospitals.

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8 Gynecologists questionnaire

We conducted a survey among members of the Portuguese Society of Urogynecology (PSUG), which is integrated in Portuguese Society of Gynecology (SPG) and the International Urogynecological Association (IUGA), as an affiliated society. The survey was aimed at reviewing the current practices on POP surgical procedures, including the use of meshes. It was also aimed at evaluating the impact of FDA 2011 communication on mesh use [10].

All PSUG members, gynecologists with special interest in urogynecology, were invited via email to participate in this survey. The initial invitation was sent in May 2013. Three waves of reminders were sent to non-respondents, and the survey was closed on November 2013.

The questionnaire collected basic demographic and professional information, including sex, type of practice, and number of years in practice. Respondents who reported performing POP surgery were asked questions relating to the frequency of use of current POP procedures. Participants were asked about the use of meshes before and after 2011 FDA communication [10]. Then they were requested to estimate the total number of POP surgeries performed per year with vaginal and abdominal mesh.

Statistical Methods

Non-parametric tests (Kruskal-Wallis test) were used to study differences for age and length of hospital stay over the 13-year period. Pearson's chi-square test and Fisher’s exact test with exact p-values were used to study differences in proportions. Linear regression was used to investigate genital prolapse trends among age classes and trends in POP surgical procedures. Statistical analyses were performed at a level of significance of 5%. These analyses were conducted using SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, New York, USA).

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RESULTS

Pelvic organ prolapse trends

From 2000 to 2012, 46,819 discharges with diagnoses of principal or secondary genital prolapse (ICD-9-CM codes 618.xx) were registered in Portuguese public hospitals. As shown in Table 2, the total number of hospital admissions due to genital prolapse increased from 2,368 to 4,941 (an increase of 105% from 2000 to 2012).

As illustrated in Figure 1, the number of women hospitalizations with genital prolapse per 100,000 inhabitants (2000-2012) with ages in the ranges 55-64 and 65-74 is clearly higher than in other age groups and increased over the study period. For women with ages <45 years old a slight increase in diagnosis of genital prolapse over the years is also seen, but it is considerably smaller than in other age groups.

The mean age of women undergoing prolapse surgery was 63.1±11.5 years, with a significant mean age increase from 61.9 to 63.7 years over the 13-year study period (p<0.001). A significant decrease in the length of patient hospitalization was observed over the study period, with a median length stay of 6 days in 2000 (interquartile range 4–8) and 4 days in 2012 (interquartile range 3–5), p<0.001.

The most common surgical procedures considering all episodes with an ICD-9-CM code diagnosis of genital prolapse were: repair of cystocele and/or rectocele; vaginal hysterectomy; stress urinary incontinence repair associated with genital prolapse; other repair of vagina; vaginal suspension and fixation; and operations on cul-de-sac (Figure 2). The number of native tissue anterior/posterior repairs (repair of cystocele and/or rectocele) increased significantly over time, comprising 1,140 repairs in 2000 and 3,280 in 2012. Thus, native tissue anterior/posterior repair was the most common type of surgery with 30,169 cases and presented one of the highest growths (Figure 2). Vaginal hysterectomy, repair of stress urinary incontinence, vaginal

suspension and fixation, and operations on cul-de-sac also significantly increased from 2000 to 2012 (Figure 2). The number of other repairs of vagina

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10 (colpoperineoplasty/repair of old obstetric laceration of vagina), which were frequent surgeries in the past, decreased significantly during the study period (Figure 2).

The number of obliterations of vaginal vault and obliterations of vagina, was 366 and 169 respectively along the study period, and the number of other uterine

suspensions (hysteropexy, Manchester operation, and plication of uterine ligaments) was 329. The amputation of cervix was seldom used (100 surgeries in 13 years).

The registry of POP surgeries with meshes began only in 2007. This type of prolapse repair was recorded from 2007 to 2012 in a total of 1,468 cases, representing 6% of total prolapse diagnosis. The cystocele repair with mesh was the most frequent surgical mesh procedure, with 700 cases and representing 48% of all surgical mesh procedures in this period.

Regarding the anterior/posterior compartment, cystocele repair with mesh represented 10% of all cystocele repair surgeries, and rectocele repair with mesh represented 7% of all rectocele repair surgeries. However, the simultaneous repair of cystocele and rectocele with mesh was less frequent, representing only 3% (Figure 3B). It is noted that anterior/posterior repairs with native tissue were not only more frequent but also showed higher growth than anterior/posterior repairs with vaginal meshes. Regarding the apical compartment, vaginal suspension and fixation with mesh represented 11% of all vaginal suspensions and fixation surgeries, and other

operations on de-sac with mesh represented only 1% of all other operations on cul-de-sac (Figure 3C).

The total number of mesh prolapse repairs increased significantly over time from 5 mesh repairs in 2007 to 468 in 2011; from 2011 to 2012, a smaller increase to 497 was registered (Figure 3A). When analyzed by vaginal compartment, mesh use for prolapse increased consistently apical compartment repair (Figure 3C); however, for anterior/posterior compartment repair, mesh use peaked in 2011 and then slightly declined in 2012 (Figure 3B).

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11 Thus, and regarding the impact of 2011 FDA communication on the use of mesh for POP surgery, the following variations from 2011 to 2012 were observed: repair of cystocele graft or prosthesis from 243 to 223 (p=0.241); repair of rectocele with graft or prosthesis from 97 to 87 (p=0.377); repair of cystocele and rectocele with graft or prosthesis from 54 to 62 (p=0.524); vaginal suspension and fixation with graft or prosthesis from 73 to 122 (p=0.001); and other operations on cul-de-sac with graft or prosthesis from 1 to 3 (p=0.625).

Current practices on pelvic organ prolapse surgery

The questionnaire was sent to the 55 members of Portuguese Society of

Urogynecology. With 46 respondents, the response rate was 84%. All of them reported performing prolapse surgery. The demographic characteristics of the respondents are summarized on Table 3. The survey respondents, representing a wide range of years of practice and practice type, reported performing a mean of 20.8 (min:0, max:100) POP vaginal mesh surgeries per year and a mean of 4.2 (min:0, max:30) POP abdominal mesh surgeries per year.

For surgical procedures frequently used to treat utero-vaginal prolapse uterine descent, according to three/four stage descent, the principal choices were: vaginal hysterectomy with or without anterior/posterior repair (n=20, 45%), vaginal

hysterectomy with sacrospinous ligament fixation (n=15, 33%), and vaginal

hysterectomy associated to McCall culdoplasty (n=11, 24%); whereas, vaginal mesh repair not associated to hysterectomy was referred only by 1 of the respondents (2%).

In the case of apical compartment vaginal vault prolapse (three/four stage), the principal choices were: anterior/posterior repair with sacrospinous fixation (n=15, 33%), abdominal sacrocolpopexy (n=11, 24%), and vaginal mesh repair (n=8, 17%).

Among the respondents, anterior colporraphy (n=35, 76%), vaginal paravaginal repair (n=20, 43%), and anterior repair with vaginal mesh (n=8, 17%) were the most frequently used for anterior vaginal wall prolapse procedures. For the posterior wall

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12 prolapse, the most frequently used procedures were: traditional posterior colporraphy (n=36, 78%), site-specific defect repair (n=23, 50%), and posterior repair with vaginal mesh (n=5, 11%).

It was observed that 57% (26/46) of the respondents performed POP vaginal mesh surgery. Of those, 11 (42%) never performed sacrospinous ligament fixation and 16 (62%) never performed vaginal paravaginal repair. While from those who did not perform POP vaginal mesh surgery, only 4 (20%) never undertook sacrospinous ligament fixation (p=0.072) and all of them reported having done vaginal paravaginal repair (p<0.001), with 16 (80%) referring that it is performed frequently.

After 2011 FDA communication, 27% (7/26) of the respondents reported having changed POP surgical procedures with vaginal meshes, whereas 73% (19/26) still use mesh with no change in practice. From those that changed their surgical practice with vaginal meshes, 4 (57%) reported a reduced use of meshes, 2 (29%) stopped using meshes, and 1 (14%) mentioned other actions. There was no statistically significant difference among male and female gynecologists, years in practice, practice type, and number of POP vaginal and abdominal mesh surgeries performed per year, between gynecologists who changed their practice after FDA’s communication and those who did not change.

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DISCUSSION

The total number of hospital admissions due to POP registered in Portugal increased 105% from 2000 to 2012. This increased number of diagnoses can be explained not only by a greater awareness of the population (which leads women to seek medical help more promptly), but also by a greater awareness of professionals and the availability of better surgical therapeutic techniques.

Studies conducted in other countries exhibited similar results [15,16]. In the Netherlands, hospital admissions due to uterovaginal prolapse increased 65% during the period 1997-2009 [16]. In the US, the number of women undergoing prolapse surgeries, is also reported to have slightly increased from 1998-2007 [15]. However, a more comprehensive US analysis from 1979-2006 [17] showed a different trend, reporting that the number of women undergoing prolapse procedures in the US, decreased 23.6% from 1979-2006. Nevertheless, when stratified by age, the age-adjusted rates for inpatient procedures for prolapse remained stable for women with ages ≥52 years and decreased by two-thirds, for women with ages <52 years.

In this study, the number of women subjected to prolapse repair surgeries in the age groups 55-64 years and 65-74 years had the largest increase over 13-year period, whereas women with ages <45 years only showed a slight increase. Additionally, the mean age of women undergoing prolapse surgery increased from 2000 to 2012, which is consistent with findings from other studies [17]. It is, however, noteworthy that even though the age of women subjected to prolapse surgery increased, the length of hospitalization decreased, which is in line with studies from other countries [17]. This increase in mean age of women undergoing prolapse surgery can be explained by several factors: the population is aging; there is increased awareness among older women; and surgical techniques evolved, providing now better results in these patients. In Portugal, women with ages ≥65 years represented already 19.4% of the population

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14 in 2012 [18], and in line with this aging population trend, Luber et al [19] estimate that by 2030 diagnosis of pelvic floor disorders will increase substantially.

Our findings indicate that surgical trends in treating POP evolved in the last 13 years in Portugal. The repair of cystocele and/or rectocele with native tissues was the most common POP surgery, showing the greatest growth; this is in accordance with the study conducted in the Netherlands from 1997 to 2009, which also showed a marked increase of anterior and/or posterior colporraphy [16].

Vaginal hysterectomy was the second most common type of surgery, with a substantial growth over the study period. In a comparable study from the UK, regarding women with uterovaginal prolapse, the procedure of choice was vaginal hysterectomy and repair [20]. Comparing our Portuguese data on vaginal hysterectomy with data from other countries, we noticed that some studies mention decreases of vaginal hysterectomy over the years [21,22]. Ping Wu et al. reported changing trends of surgical procedures used for uterine prolapse in Taiwan from 1997-2007, with a trend for increased use of uterine suspension with uterine preservation, and a decreasing trend for overall hysterectomy [22]. Detollenaere et al. [16] in the Netherlands referred that vaginal hysterectomy was the most frequently performed surgical intervention for uterine descent, however a trend toward preserving the uterus was observed.

Concomitant anti-incontinence surgery was the third most frequent type of surgery, also with a substantial growth over the study period. Rogo-Gupta et al. [23], identified 42.6% women undergoing concurrent incontinence surgery when analyzing women who underwent POP repair. A possible explanation for this concomitant POP surgery is the fact that our dataset comprises not only inpatient data, but also

ambulatory surgical procedures. This is in line with the work of Erekson [23], who reported an increased number of women undergoing ambulatory surgical procedures for pelvic floor disorders from 1996 to 2006 in the US.

The use of surgical mesh for POP repair in Portugal is very limited, in comparison with traditional non-mesh repair. Nonetheless, the use of surgical mesh for POP repair

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15 has clearly increased from 2007 to 2011, with a smaller increase from 2011 to 2012. These increases are not entirely in agreement with other studies. Here, we identified a plateau of mesh procedures in 2011, whereas in other countries, vaginal mesh use for POP repair has been found to stabilize around 2007-2009 [5,24]. Nevertheless, the use of meshes in POP repair in Portugal is clearly smaller than the use of meshes identified in other studies [5,23-25], and therefore the trends observed in the US, are not

comparable to data from Portugal and or even the Netherlands [16], since here mesh use is not so widespread.

When mesh use is analyzed by prolapse compartment there is a marked and significant increase of mesh use for anterior/posterior repairs, with a peak in 2011 and a slight decrease after 2011 to 2012. For apical compartment repair this increase is constant and significant from 2007 to 2012. However, it is important to note that the inadequacies of the current coding practices impair a more precise analysis. In fact, apical compartment mesh repair (vaginal suspension and fixation and operations on cul-de-sac) uses ICD-9-CM codes that do not allow categorization as abdominal or vaginal mesh surgery. This has practical implications, since the codes can also reflect abdominal prolapse repair, which are out of scope of the FDA communications. It is possible that a transition from vaginal to abdominal meshes is disguised in this continuous increase mesh use for apical repairs. Therefore, in order to obtain more data that might help to clarify the surgical management of POP and the impact of FDA communications on surgical practices in Portugal, we decided to conduct a survey of among the members of PSUG.

Among the gynecologists who accepted to answer the questionnaire, different surgeries were selected as procedures frequently used to treat POP in the various compartments; but POP surgeries with vaginal mesh were rarely referred as

procedures of choice. These findings are mostly in agreement with previous studies [16,20], and reflect the wide variety of procedures implemented in the surgical treatment of POP, but also the limited use of vaginal meshes.

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16 About half the respondents (57%) performed POP vaginal mesh surgery.

Interestingly, among those there was a higher proportion of gynecologists who never performed vaginal paravaginal repair or sacrospinous ligament fixation. This may suggest that gynecologists who perform POP vaginal mesh surgery are less familiarized with traditional non-mesh procedures.

Only a small proportion of respondents (27%) who performed POP vaginal mesh surgery, actually reported having changed their practice after FDA 2011

communication. These findings suggest that the impact of FDA communication was less pronounced among Portuguese gynecologists. In a previous study conducted in the US, only 21% of respondents reported not having change their practices [11]. It is, however, noteworthy that in Portugal the overall use of vaginal mesh is much smaller than in the US, which may justify why Portuguese gynecologists did not felt the need to change their practices.

The main weakness of this study is transversal to all studies that comprise surveys: they depend on the accuracy and objectivity (or lack of it) of respondents. However, in this case the response rate was remarkably high (84%), which is an indicative that the patterns identified here are representative of the population. As in other studies, we also had to face the limitations of ICD-9-CM coding. This coding system does not distinguish the type of apical suspension performed, and does not consistently categorizes mesh procedures by abdominal or vaginal route. This system allows, however, classification of the type of mesh used (synthetic vs. biological), but this property was not registered at Portuguese hospitals, and therefore it was not possible to assess the types of meshes used. Additionally, mesh use might have been underreported in the first years after it was introduced in the coding system (2007– 2008). Nevertheless, the main trend of increased use of meshes up to 2011 cannot be only attributed to this underreporting issue, since the growth in mesh use was

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17 The main strength of this study is the use of the Portuguese National Medical Registry database, which provides nationally representative and validated data. Besides, the time period under analysis is fairly long (13 years), allowing a

comprehensive characterization of the evolution of surgical management of POP in Portugal.

In conclusion, POP surgical procedures conducted in Portugal greatly increased in the last decade. The use of surgical meshes is still limited, but despite FDA safety communication, it has increased over the years. Nonetheless, mesh use has only slight increased from 2011 to 2012, and therefore further analyses will be required to assess the full impact of FDA safety communications.

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ACKNOWLEDGEMENTS

The authors would like to thank the Central Administration of the National Health System (Administração Central do Sistema de Saúde) for providing access to the Portuguese National Medical Registry (clinical-administrative data).

FUNDING

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21 16. Detollenaere RJ, den Boon J, Kluivers KB, Vierhout ME, van Eijndhoven HW

(2013) Surgical management of pelvic organ prolapse and uterine descent in the Netherlands. International urogynecology journal 24 (5):781-788.

doi:10.1007/s00192-012-1934-5

17. Jones KA, Shepherd JP, Oliphant SS, Wang L, Bunker CH, Lowder JL (2010) Trends in inpatient prolapse procedures in the United States, 1979-2006. American journal of obstetrics and gynecology 202 (5):501 e501-507.

doi:10.1016/j.ajog.2010.01.017

18. Instituto Nacional de Estatística (2013) Estatísticas Demográficas 2012.

19. Luber KM, Boero S, Choe JY (2001) The demographics of pelvic floor disorders: current observations and future projections. American journal of obstetrics and gynecology 184 (7):1496-1501; discussion 1501-1493

20. Jha S, Moran P (2011) The UK national prolapse survey: 5 years on. International urogynecology journal 22 (5):517-528. doi:10.1007/s00192-011-1379-2

21. Babalola EO, Bharucha AE, Melton LJ, 3rd, Schleck CD, Zinsmeister AR, Klingele CJ, Gebhart JB (2008) Utilization of surgical procedures for pelvic organ prolapse: a population-based study in Olmsted County, Minnesota, 1965-2002. International urogynecology journal and pelvic floor dysfunction 19 (9):1243-1250.

doi:10.1007/s00192-008-0613-z

22. Wu MP, Huang KH, Long CY, Tsai EM, Tang CH (2010) Trends in various types of surgery for hysterectomy and distribution by patient age, surgeon age, and hospital accreditation: 10-year population-based study in Taiwan. Journal of minimally invasive gynecology 17 (5):612-619. doi:10.1016/j.jmig.2010.04.010

23. Rogo-Gupta L, Rodriguez LV, Litwin MS, Herzog TJ, Neugut AI, Lu YS, Raz S, Hershman DL, Wright JD (2012) Trends in surgical mesh use for pelvic organ prolapse from 2000 to 2010. Obstetrics and gynecology 120 (5):1105-1115. doi:10.1097/AOG.0b013e31826ebcc2

(27)

22 24. Jonsson Funk M, Edenfield AL, Pate V, Visco AG, Weidner AC, Wu JM (2013)

Trends in use of surgical mesh for pelvic organ prolapse. American journal of obstetrics and gynecology 208 (1):79 e71-77. doi:10.1016/j.ajog.2012.11.008 25. Reynolds WS, Gold KP, Ni S, Kaufman MR, Dmochowski RR, Penson DF (2013)

Immediate effects of the initial FDA notification on the use of surgical mesh for pelvic organ prolapse surgery in medicare beneficiaries. Neurourology and urodynamics 32 (4):330-335. doi:10.1002/nau.22318

(28)

23

FIGURE LEGENDS

Figure 1 - Number of hospitalizations with genital prolapse diagnosis per 100,000 inhabitants

(2000-2012), stratified by age groups.

Figure 2 - Trends in surgical procedures for genital prolapse.

Figure 3 - Trends in mesh use for prolapse repair. (A) Overall and by compartment mesh use

trends. (B) Trends for anterior/posterior compartment prolapse repairs with and without mesh.

(29)

24

TABLES

Table 1 - Selected surgical procedures considering all episodes with an ICD-9-CM code of genital

prolapse

Procedure description ICD-9-CM Code

Anterior/Posterior compartment repair

Repair of cystocele and rectocele 70.50

Repair of cystocele 70.51

Repair of rectocele 70.52

Repair of cystocele and rectocele with graft or prosthesis*” 70.53 Repair of cystocele with graft or prosthesis*” 70.54 Repair of rectocele with graft or prosthesis*” 70.55 Apical compartment repair

Repair of uterine supporting structures - interposition operation 69.21 Other uterine suspension (hysteropexy, Manchester operation and plication of the uterine ligaments) 69.22 Other repair of uterus and supporting structures 69.29 Other operations on supporting structures of uterus 69.98

Vaginal suspension and fixation 70.77

Vaginal suspension and fixation with graft or prosthesis*” 70.78

Other operations on cul-de-sac 70.92

Other operations on cul-de-sac with graft or prosthesis*” 70.93 Hysterectomy procedure

Subtotal abdominal hysterectomy 68.3

Laparoscopic supracervical hysterectomy (LSH) 68.31 Other and unspecified subtotal abdominal hysterectomy 68.39

Total abdominal hysterectomy 68.4

Laparoscopic total abdominal hysterectomy 68.41 Other and unspecified total abdominal hysterectomy 68.49 Laparoscopically assisted vaginal hysterectomy (LAVH) 68.51 Other and unspecified vaginal hysterectomy 68.59 Other and unspecified hysterectomy 68.9 Incontinence procedure

Plication of urethrovesical junction 59.3

Suprapubic sling operation 59.4

Retropubic urethral suspension 59.5

Paraurethral suspension 59.6

Levator muscle operation for urethrovesical suspension 59.71 Other repair of urinary stress incontinence 59.79 Others procedures

Repair of rectum 48.7

Amputation of cervix 67.4

Obliteration and total excision of vagina (vaginectomy) 70.4

Vaginal reconstruction 70.62

Vaginal reconstruction with graft or prosthesis*” 70.64

Suture of laceration of vagina 70.71

Other repair of vagina (colpoperineoplasty/repair of old obstetric laceration of vagina) 70.79 Obliteration of vaginal vault (LeFort operation) 70.8

Other operations on vagina 70.91

Repair of vulva and perineum 71.7

Suture of laceration of vulva or perineum 71.71 Other repair of vulva and perineum/repair of old obstetric laceration of vulva or perineum 71.79

*Modifier indicating insertion of biological graft (ICD-9 code 70.94) "Modifier indicating insertion of synthetic graft (ICD-9 code 70.95)

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25 Table 2 - Episodes with a diagnosis of genital prolapse (ICD-9-CM code 618.xx) by discharge

year Type of diagnosis (n) 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total Principal diagnosis of genital prolapse 1986 1929 2011 2345 2599 2734 3014 3093 3278 3723 3971 4089 4069 38841 Secondary diagnosis of genital prolapse 382 437 418 472 595 618 644 621 718 717 731 753 872 7978 Total 2368 2366 2429 2817 3194 3352 3658 3714 3996 4440 4702 4842 4941 46819

(31)

26 Table 3. Demographic characteristics of the members of the Portuguese society of

urogynecology who responded to the questionnaire.

Characteristics Respondents, n (%) (n=46) Gender Male 16 (35) Female 30 (65) Years in practice < 10 12 (26) 10 to 20 21 (46) > 20 13 (28) Type of practice Public Hospital 13 (28) Private Hospital 3 (7) Both 30 (65)

POP vaginal mesh surgeries per year

0 20 (43)

1-30 17 (37)

> 30 9 (20)

POP abdominal mesh surgeries per year

0 13 (28)

1-10 29 (63)

(32)

27 Figure 1

(33)

28 Figure 2

(34)

29 Figure 3

(35)

Agradecimentos

À Professora Doutora Amélia Ricon Ferraz, Orientadora da presente tese, agradeço a

sua conduta de alto valor científico, bem como a permanente atenção e

disponibilidade demonstradas. Gostaria destacar a figura modelar em termos

intelectuais e humanos e exprimir o meu orgulho e satisfação por ter aceitado o meu

pedido de orientação.

À Dra. Paula Nogueira, Coorientadora da presente tese, agradeço o apoio que sempre

me transmitiu, a orientação e cooperação concedidas na concretização deste projeto.

À minha Faculdade, minha “alma mater”, pela formação de excelência que me

proporcionou.

À Dra Mariana Maia, que pela disponibilidade incondicional, apoio e carinho foi uma

ajuda inestimável em todo o meu percurso académico.

Aos meus Pais, expressar a minha admiração e gratidão pela confiança, encorajamento

e palavras de incentivo mas sobretudo, pela referência que para mim constituem.

Aos meus Avós, pela sabedoria transmitida, esta tese é vossa em agradecimento por

todo o vosso amor

(36)

Editors-in-Chief

Peter Dwyer

pdwyer@connexus.net.au

Paul Riss

paul.riss@gmail.com

Editorial Office

Roisin Stewart

iujeditorialoffice@gmail.com

Article Types and Submission Process

The International Urogynecology Journal (IUJ) accepts original articles, case reports, reviews

(including mini reviews), clinical opinions, editorials, controversies in urogynecology, and video.

Original articles must present scientific results that are essentially new. All manuscripts are subject

to peer review. All manuscripts must be submitted electronically through Editorial Manager at

http://www.editorialmanager.com/iujo,

or

through

the

Springer

website:

http://www.springer.com/medicine/gynecology/journal/192. Manuscripts submitted by regular

mail will not be reviewed and will not be returned. Authors will be notified by email to submit

electronically. If you have any questions regarding manuscript submission, please contact the

IUJ Editorial Office by email at iujeditorialoffice@gmail.com.

Authorship and Copyright and Financial Disclosure/Conflict of Interest Form

All submissions must include a completed Authorship and Copyright and Financial

Disclosure/Conflict of Interest Form. The corresponding author can complete the copyright

portion of the form. All authors must complete and sign the conflict of interest and authorship

portion of the form. The Authorship and Copyright and Financial Disclosure/Conflict of Interest

Form can be obtained at the Editorial Manager login site:

http://www.editorialmanager.com/iujo

,

or on the Springer website:

http://www.springer.com/medicine/gynecology/journal/192

. The

Authorship and Copyright and Financial Disclosure/Conflict of Interest Form must be submitted

(37)

electronically at the time of manuscript submission, without exception. In addition to this form,

the title page must include a conflict of interest statement for each author.

Patient Confidentiality

Patients have a right to privacy; identifying information, including names, initials, or hospital

numbers, should not be published in written descriptions, photographs, videos, or pedigrees

unless the information is essential for scientific purposes and the patient (or parent or guardian)

gives written informed consent for publication. Patient consent should be written and available to

the IUJ Editors upon request.

For case reports and video articles, authors must obtain written consent from the patient. All

authors must include a statement before the References section under the heading ‘Consent’

which reads: ‘Written informed consent was obtained from the patient for publication of this case

report/ video article (please delete as appropriate) and any accompanying images.’

Review Process

Once a manuscript has been submitted, the corresponding author will be contacted by email.

Manuscripts that do not conform to the journal style (see Manuscript Preparation below) will be

returned to the corresponding author for revision and resubmission online, prior to being

considered for publication.

Manuscripts which do not meet the general criteria for this journal will be returned to the

corresponding author without undergoing peer review and will not be accepted. This decision will

be made by the Editors-in-Chief. Criteria include but are not limited to:

 relevance to the aims of the journal with the topic being of overall general interest

 sufficiently original and contributing to the advancement of the field

 clearly written with appropriate study methods, well-supported data and conclusions

which are supported by the data

 clear and understandable English, grammar, and spelling

Once a manuscript has been submitted, conforms to journal style, and is deemed appropriate for

this journal, it will be assigned to an editor and begin to go through the peer review process. The

corresponding author will be contacted by email with editorial decisions as the manuscript moves

through the peer review process.

Manuscripts that are returned to the corresponding author with Major Revisions or Minor

Revisions, will include the reviewers' and the editor's comments and suggestions for changes. The

notification will include the option for the corresponding author to accept or decline submitting a

revised manuscript and addressing the reviewers' comments, as well as the deadline for

resubmitting a revised manuscript. All revised manuscripts will be submitted online via Editorial

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Manager. Revised manuscripts should clearly show where revisions have been made by using

the Track Editing option in Microsoft Word, and include a cover letter addressing each

reviewer's point with a counterpoint. Manuscripts which have been returned with a decision of

Major Revisions or Minor Revisions are not guaranteed acceptance after a revised manuscript has

been resubmitted. Revised manuscripts will go through the peer review process. Manuscripts

which have been reviewed and a decision for revisions (major or minor) has been made may be

considered as new submissions if not resubmitted within three months from the time of

notification. Requests for extension of the resubmission deadline should be directed by email to

the Editorial Office.

Redundant, Duplicate, or Fraudulent Publication

Authors must not simultaneously submit their manuscript to another journal if that manuscript is

under consideration by the International Urogynecology Journal (IUJ). Redundant or duplicate

publication is considered as a manuscript that overlaps substantially with one already published in

print or electronic media. At the time of manuscript submission, authors must inform the editor

about all submissions and previous publications that might be regarded as redundant or duplicate

publication of the same or very similar work. Any such publications must be referred to and

referenced in the new manuscript. Copies of such material should be included with the submitted

manuscript as a "supplemental file".

Authors must not:

 Willfully and knowingly submit false data

 Submit data from a source not the authors' own

 Submit previously published material (with the exception of abstracts) without correct and

proper citation

 Omit reference to the work of other investigators that establishes a priority

 Falsely certify that the submitted work is original

 Use material previously published elsewhere without prior written approval of the

copyright holder

Please refer to Publishing Integrity for a detailed explanation on Publishing Ethics (full policy

available at the IUJ Homepage).

Confidentiality

All manuscripts are treated by the assigned reviewers as privileged and confidential information.

Reviewers may request advice from another party, subject to the general principles of

confidentiality and permission of the managing editor. Reviewers' comments are not published or

made available publicly except with the prior written permission of the reviewer, author, and

editor. However, reviewers' comments are shared with the other reviewers of the same

(39)

manuscript, and reviewers will be notified of the editor's decision. The reviewers' identity remains

anonymous. All reviewers are asked to disclose any potential conflict that could influence their

opinions of manuscripts, prior to review of a manuscript. Editors will only disclose information

pertaining to a specific manuscript (i.e. receipt, status in review process, content, criticism, or final

decision) to the author and reviewers.

Manuscript Preparation

Manuscripts must be written in clear, concise English and conform to the specifications described

herein. Manuscripts that are considered poor quality in terms of English, grammar, and spelling

and require extensive revisions for clarity may be returned to the author for revision prior to

proceeding to the peer review process. Springer offers a manuscript revision service through

Edanz, and can be accessed through a link on the IUJ Springer homepage. Edanz may also be

accessed directly at

www.edanz.com

. This is associated with a fee for service, which is the

author’s responsibility.

Terminology

It is suggested that “Methods, definitions, and units conform to the standards jointly

recommended by the International Urogynecological Association and the International Continence

Society and , except where specifically noted” (Haylen et al. An International Urogynecological

Association (IUGA)/International Continence Society (ICS) joint report on the terminology for

female pelvic floor dysfunction. Int Urogynecol J 2010;21:5-26.

All manuscripts that have been accepted for publication are subject to copy-editing.

Article Types and Specific Requirements

Original Articles

 Title page:

o all authors and affiliations

o

corresponding author contact information (email mandatory)

o

conflict of interest statement for each author

o

each author’s participation in the manuscript

 Structured abstract (250 words) and Keywords (up to 6)

 Brief summary (25 words)

 Word limit of 4000 words (average is 2000 words)

 Maximum of 6 authors (more than 6 authors requires submission of a letter to the

editorial office explaining the reasons)

 Maximum of 30 references

 Maximum of 6 figures/tables (If the article contains a large number of illustrations

then the length of the text should be adjusted accordingly to a lower word count)

(40)

Review Articles

 Title page:

o

all authors and affiliations

o

corresponding author contact information (email mandatory)

o conflict of interest statement for each author

o

each author’s participation in the manuscript

 Structured abstract (250 words) and Keywords (up to 6)

 Brief summary (25 words)

 Word limit of 6000 words

 Maximum of 3 authors

 Maximum 100 references

 Maximum of 10 figures

Case Reports

 Title page:

o

all authors and affiliations

o corresponding author contact information (email mandatory)

o

conflict of interest statement for each author

o

each author’s participation in the manuscript

 Abstract (50 – 150 words) to include case/conclusions and Keywords (up to 6)

 Brief Summary (25 words)

 Word limit of 1000 words

 Maximum of 3 authors

 Maximum of 1-2 figures/tables

 Maximum of 5 references

Current Opinion/Updates

 Title page:

o All authors and affiliations

o

corresponding author contract information (email mandatory)

o

conflict of interest statement for each author

o each author’s participation in the manuscript

 Unstructured abstract (50 – 150 words) and Keywords (up to 6)

 Word limit of 3000 words

 Maximum of 7 authors

 Maximum of 25 references

(41)

Letters to the Editor (Comments)*

 Title and corresponding author

 Word limit of 400 words

 Maximum of 5 references (the first reference must be the publication in question if

letter relates to a publication)

*NOTE: The editorial staff reserves the right to shorten letters if necessary and to make

minor editorial alterations without reference to the writer; letters may be published

together with a reply from the original author. If the original author does not respond, a

notation indicating ‘response declined’ will be published. As space for Letters-to-the-Editor

is limited, only a selection of letters submitted may be published.

Video Article

In addition to a video authors should submit a manuscript text. This should include:

 Title page (incorporating a structured abstract, keywords and references):

o

Title of video

o All authors and affiliations

o

Corresponding author contact information (email mandatory)

o

Conflict of interest statement for each author

o

Abstract (up to 200 words)

 Structured text (800-1200 words):

1. Aim of the video / Introduction

2. Method

3. Results (if presenting data)

4. Conclusion

Presenting results and using tables is encouraged.

 Keywords (up to 6)

 Up to 10 references

 Video format:

o Should not exceed 9 minutes

o

File size should not exceed 100MB

o All videos should be in MP4 format and will be playable on a Windows-based

computer

o The use of unnecessary audio (i.e. music) is discouraged

o

The content of the video file(s) must be identical to that reviewed and

accepted by the editors

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o

All narration should be in English

o Information that may identify patients, including names, initials, or hospital

numbers, should not be included in videos unless the information is essential

for scientific purposes and the patient (or parent or guardian) gives written

informed consent for publication. Patient consent should be written and

available to the IUJ Editors upon request. All authors must include a

statement before the References section under the heading ‘Consent’ which

reads: ‘Written informed consent was obtained from the patient for

publication of this video article and any accompanying images.’

Manuscript Format

The following sections must each begin on separate pages:

 Title Page*

 Abstract*

 Text (Introduction, Materials and Methods, Results, Discussion)*

 Acknowledgements

 References*

 Figure Legends (if any figures)

 Tables

 Appendices (if any)

*Mandatory sections

Manuscripts must have all pages numbered and the text should be double spaced.

Title page

The title page MUST include:

 Title - Capture the essence of the scientific contribution in no more than 15 words,

including spaces. It should be specific enough for electronic retrieval and searches

 Author Details - Name(s) and institutional affiliation(s) of all the author(s)

 Corresponding Author and contact information (address, telephone, fax, email)

 Word Count – Must be included in the lower left hand side of the title page. Word

count includes abstract and main text but not references.

 Financial Disclaimers/Conflict of Interest statement (if none, state FINANCIAL

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mandatory Copyright and Authorship Form which must be completed and included

at the time of submission.

 Each authors' contribution to the Manuscript

 List each author by surname (family name) and describe each of their contributions

(select all that apply) to the manuscript using the following terms:

Protocol/project development

Data collection or management

Data analysis

Manuscript writing/editing

Other (please specify briefly using 1 to 5 words)

(Adapted from WAME Authorship paper, www.wame.org, posted January 10, 2007)

For example:

AR Smith: Project development, Data Collection, Manuscript writing

TS Jones: Data collection

AJ Davis: Manuscript writing

Abstract

Each original article and review/mini review article must include a structured abstract of

up to 250 words that is intelligible to the journal’s general readership without reference to

the text and must reflect the content of the article accurately. All original articles and

reviews/mini reviews should present the abstract in a structured format as follows:

 Introduction and Hypothesis

 Methods (include sample size and statistical approaches).

 Results - The Results must contain sufficient data for readers to evaluate the

credibility of the conclusion. All of the data does not need to be presented. The

conclusion should be an inference, not a summary.

 Conclusions - Readers should be able to understand the question asked in the study

and why and how it was done.

Keywords

Up to 3-6 keywords should be supplied in alphabetical order after the Abstract,

characterizing

the

scope

of

the

manuscript.

Brief summary

(44)

Abbreviations

These should be defined at first mention in the abstract and again in the main body of the

text and used consistently thereafter.

Introduction

Develop the study rationale and avoid a literature review. Literature should be cited only

to the extent that helps the reader understand why the question is asked. End the

Introduction with a stated aim or question, preferably expressed as a testable hypothesis.

For example, if the study is aimed at identifying the color of apples, or asks what color are

apples, state ‘we hypothesized that apples will be green rather than red’. The reason for

this hypothesis should be contained in the rationale.

Materials and Methods

The Materials and Methods section should describe the procedures used and include

sufficient information such as subjects and measurements) so that a reader can evaluate

the credibility of results and interpretation in the light of possible methodological

limitations. Detailed statistical methods should be included. Findings should be quantified

when possible and presented with appropriate indicators of measurement error or

uncertainty, e.g. confidence intervals. The source or manufacturer name of all products

used should be stated. Authors should always consider clarity for other workers about how

and why a study was done in a particular way. All original articles should include

Ethics/Institutional Review Board (IRB) approval for all studies, human or animal. Studies

in which ethics approval does not apply or is waived by the IRB/Ethics Committee should

state this in the manuscript, and the reason for the exemption or waiver.

Randomized Controlled Trials (RCT)

In cases of prospective, randomized trials (RCT), it is strongly encouraged that they are

registered with a public clinical trial registry, such as www.clinicaltrials.gov (NO FEE) prior

to commencing patient recruitment. Proof of IRB approval is MANDATORY (or an

explanation for exemption or waiver). Authors should refer to the CONSORT statement

(http://www.consort-statement.org/), including the flow diagram and checklist

(http://www.consort-statement.org/consort-statement/overview0/#checklist)

when

preparing a manuscript reporting RCT. The flow diagram should be included as Figure 1 in

the document.

Results

Results concerning the primary testable hypothesis should be presented first. Do not ‘save

the best for last’. Data should be presented as concisely as possible, if appropriate in the

form of tables and/or graphs, although very large tables should be avoided. If authors wish

to present the full data of the study, and any technical details, these can be included as

Electronic Supplementary Material.

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Discussion

The following paragraph structure is recommended:

 Summarize the main findings from most to least important, including a statement

whether the results are consistent with the stated hypothesis.

 Discuss how the results confirm or contrast with published literature.

 If the results differ, discuss the possible reasons for this. Details of methodology and

results of published literature may be appropriate here. Avoid reviewing literature

outside the scope of the study.

 Discuss the significance and implications of this new data. Having developed the

rationale to define the limits of current knowledge, how does this new information

advance understanding?

 Write a paragraph concerning the limits of the study – this is critical. The inferences

made throughout the Discussion must be written bearing in mind the constraints of

the methodological limitations of the work. Papers written without this section will

not be considered for publication.

 Summarize and Conclude. The conclusion is an inference. Within the constraints of

the limitations of the study, the authors may boldly speculate regarding the

significance of the findings and future research.

Acknowledgements

The acknowledgements should be as brief as possible. They should include the specific

contributions of all persons who have substantially contributed to the work reported, e.g.

technical assistance, data collection, analysis, writing or editing assistance, but who do not

fulfill authorship criteria. Authors should obtain written permission from all persons listed

in the Acknowledgement section. All institutional and corporate funding sources should be

mentioned. The names of funding organizations should be written in full.

Funding

Authors are expected to disclose any commercial or other associations that might pose a

conflict of interest in connection with submitted material. All funding sources supporting

the work and institutional or corporate affiliations of the authors should be acknowledged

even if there are no conflicts of interest or disclosures and must be clearly stated within

the manuscript file.

Citation

Reference citations in the text should be identified by numbers in square brackets. Some

examples:

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