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Fistula in cleft lip and palate patients Salimi, Negar 2018

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Fistula in Cleft Lip and Palate Patients by Negar Salimi DDS, Azad University of Iran, 1996   A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Craniofacial Science)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)   August 2018    © Negar Salimi 2018   ii  The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled:  Fistula in Cleft Lip and Palate Patients submitted by Negar Salimi in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Craniofacial Sciences Examining Committee:  Dr. Sunjay Suri, External Examiner Dr. Arminee Kazanjian, University Examiner  Dr. David MacDonald, University Examiner  Additional Supervisory Committee Members:  Dr. Edwin Yen, Dentistry, Dentistry, Co-supervisor  Dr. Jolanta Aleksejuniene, Dentistry, Co-supervisor  Dr. Angelina Loo, Supervisory Committee Member       iii Abstract Introduction: The cleft lip and palate congenital malformation is a common condition, which poses a large burden of care on the young patients and their caregivers. The World Health Organization reported the prevalence of cleft lip with or without cleft palate to be 10 in 10,000 births in the United States and worldwide and 12 in 10,000 births in Canada (IPDTOC, 2011).  Post-operative palatal fistula is frequently encountered after the surgical repair of a cleft lip and palate deformity. A wide range of fistula occurrence rates, have been reported in the literature with significant variability. After conducting a systematic scoping review of the cleft palate literature we found that high quality studies were needed in this field. Additionally there were very few Canadian studies available on this subject.   We recognized the need to investigate the incidence of palatal fistula at British Columbia’s Children’s Hospital (BCCH) to be able to compare our rates with other centers worldwide.  As a result of our research, we realized a gap in the literature, which was the lack of a standardized assessment protocol for the follow up of cleft lip and palate patients.  Methods: A retrospective chart review was performed at British Columbia’s Children’s Hospital to examine the incidence of palatal fistula in children with non-syndromic clefts and to identify determinants associated with higher fistula rates. In preparation for the protocol development we conducted electronic database searches and contacted 13 major cleft centers worldwide.  iv Conclusion: The systematic review concluded that the research mainly focused on surgeries and fistula-related risk determinants. The level of evidence was low and the quality was poor. No consistent pattern was detected between fistula occurrence and any of the studied risk determinants.   The medical chart audit determined that almost a quarter of patients at BCCH presented with a palatal fistula. The significant risk determinants were severity of the cleft, less experienced surgeons, and the time period in which surgeries were performed.  The structured protocol was developed and it will help facilitate data collection of cleft patients prospectively and prevent deficiencies in current medical reporting.             v Lay Summary Study Questions: Palatal fistula is a common side effect of cleft palate surgery.  What is the quality of evidence surrounding post-operative palatal fistula in cleft patients? What is the incidence of fistula at British Columbia’s Children’s Hospital (BCCH)? What are the factors that contribute to this surgical failure? Is there a protocol for the comprehensive follow-up of cleft lip and palate patients?  Results:  Project 1: A systematic review found substantial variety in the literature in regards to the incidence of fistula. The level of available evidence in this field was low.  Project 2: An eighteen years medical chart audit of non-syndromic cleft lip and palate patients at BCCH showed that almost 1 in 4 cleft patients presented with post-operative palatal fistula after cleft surgery.   Project 3: A standardized assessment follow-up form was developed in order to systematically report all potential contributing factors to fistula development.        vi Preface This thesis is an original intellectual product of the author, Negar Salimi. The study (Project 2) was approved by the University of British Columbia’s Research Ethics Board certificate (H12-02240). Chapter 2 has been published (Salimi N, Aleksejuniene J, Yen EH, Loo AY. Fistula in cleft lip and palate patients—a systematic scoping review. Ann Plast Surg. 2017;78:91-102). Jolanta Aleksejuniene and Negar Salimi were the two independent investigators, responsible for all major areas of the project design, concept formation, data collection and analysis, as well as manuscript preparation. Jolanta Aleksejuniene also contributed to evaluation of the level of evidence and data synthesis. Edwin Yen and Angelina Loo were involved throughout the project with their feedback. Chapter 3 has been published (Salimi N, Aleksejuniene J, Yen EH, Loo AY. Time Trends and Determinants of Fistula in Cleft Patients at BC Children’s Hospital, Canada: A Retrospective 18-Year Medical Chart Audit. Cleft Palate–Craniofacial Journal 2016 e-pub). Negar Salimi was the lead investigator, responsible for all major areas of concept formation, data collection and analysis, as well as the majority of manuscript composition. Jolanta Aleksejuniene was the supervisory author on this project and was involved throughout the project in concept formation, data analysis, and manuscript preparation. Edwin Yen was involved in concept formation and Angelina Loo contributed to concept formation and was the lead investigator’s liaison at BCCH. Chapter 4 has been published in (Salimi N, Aleksejuniene J, Yen EH, Loo AY.  vii  A Standardized Protocol for the Prospective Follow-Up of Cleft Lip and Palate Patients. Cleft Palate–Craniofacial Journal 2018 e-pub). Negar Salimi was the lead investigator, responsible for all major areas of concept formation, data collection and analysis, as well as the majority of manuscript preparation. Jolanta Aleksejuniene was the supervisory author on this project and was involved throughout the project in concept formation, data analysis, and manuscript preparation. Edwin Yen and Angelina Loo were involved throughout the project in concept formation.                  viii Table of Contents Abstract .............................................................................................................................. iii	Lay Summary ...................................................................................................................... v	Preface ................................................................................................................................ vi	Table of Contents ............................................................................................................ viii	List of Tables ...................................................................................................................... xi	List of Figures ................................................................................................................... xii	List of Abbreviations ....................................................................................................... xiii	Acknowledgements .......................................................................................................... xiv	Dedication ......................................................................................................................... xv	Chapter 1: Introduction .................................................................................................... 1	1.1 Cleft Palate Deformity ............................................................................................... 1	1.2 Techniques Used to Repair Cleft Palates .................................................................. 1	1.3 Alveolar Bone Grafting ............................................................................................. 3	1.4 Post-operative Palatal Fistula .................................................................................... 5	1.4.1 Patient Related Outcomes ................................................................................... 6	1.4.2 Factors Associated with Fistula Occurrence ...................................................... 7	1.4.3 Recurrence of Fistulas ...................................................................................... 10	1.5 Study Rationale ....................................................................................................... 11	1.6 Research Question ................................................................................................... 13	1.6.1 Specific aims .................................................................................................... 13	Chapter 2: .......................................................................................................................... 14	2.1 Introduction ............................................................................................................. 14	 ix 2.2 Methods ................................................................................................................... 18	2.2.1 Preparation Phase ............................................................................................. 19	2.2.2 Assessment Phase ............................................................................................. 23	2.2.3 Knowledge Synthesis Phase ............................................................................. 24	2.3 Results ..................................................................................................................... 25	2.3.1 Assessing the levels of available evidence about fistula in cleft lip and palate patients ....................................................................................................................... 25	2.3.2 Identification of main research areas ................................................................ 28	2.3.3 Assessment of the quality of evidence in main research areas based on original studies ........................................................................................................................ 29	2.3.4 Knowledge Synthesis ....................................................................................... 37	2.4 Discussion ................................................................................................................ 51	2.5 Conclusions ............................................................................................................. 55	Chapter 3: Time trends and determinants of fistula in cleft patients at BC Children’s Hospital, Canada. A Retrospective 18 Year Medical Chart Audit. ................................... 56	3.1 Introduction ............................................................................................................. 56	3.2 Materials and Methods ............................................................................................ 58	3.3 Results ..................................................................................................................... 62	3.4 Discussion ................................................................................................................ 70	3.5 Conclusions ............................................................................................................. 73	Chapter 4: A standardized protocol for the prospective follow-up of cleft lip and palate patients ............................................................................................................................... 74	4.1 Introduction ............................................................................................................. 74	 x 4.2 Protocol development and phases ........................................................................... 80	4.2.1 Phase 1: Preparation ......................................................................................... 80	4.2.2 Phase 2: Identifying potential risk determinants .............................................. 82	4.2.3 Phase 3: Standardized protocol for the prospective follow-up of cleft lip and palate patients ............................................................................................................ 85	4.3 Discussion ................................................................................................................ 85	4.4 Conclusion ............................................................................................................... 87	Chapter 5:  Post-operative Palatal Fistula, Our Knowledge and Our Needs. .................... 88	Bibliography .................................................................................................................... 103	Appendix A: Standardized Cleft Lip and Palate Patient Assessment Form  ................... 132	Appendix B: Cleft Patient Caregiver Orientation Section .............................................. 140	    xi List of Tables Table 2- 1 Inclusion and exclusion criteria employed for the selection of relevant studies ................................................................................................................................... 22	Table 2- 2 Quality assessment of cleft lip and palate repair studies (Surgery studies: N≥30) ......................................................................................................................... 30	Table 2- 3Table 2-3. Quality assessment of studies examining fistula related risk determinants in cleft lip & palate patients (Risk Studies: N≥30) .............................. 32	Table 2-4 Internal and External Validity Assessments (all surgery & risk studies included) .................................................................................................................... 34	Table 2-5  Small studies: N< 30 patients ........................................................................... 37	Table 2- 6 Cleft lip and palate related surgery studies that reported on N≥30 patients .... 40	Table 2-7 Cleft lip and palate related risk studies that reported on N≥30 patients ........... 46	 Table 3-1 Risk determinants of fistula occurrence in cleft patients operated at British Columbia’s Children’s Hospital, Canada  (Bivariate Analyses)^ ............................. 60	Table 3-2 Risk determinants of fistula occurrence in cleft patients operated at British Columbia’s Children’s Hospital, Canada .................................................................. 67	    xii List of Figures Figure 2- 1 Flow Chart: data Search, extraction, selection, assessments and analyses ..... 21	Figure 2- 2 Hierarchy of Evidence- Fistula Occurrence in Cleft Lip & Palate patients .... 26	Figure 2- 3. Reported Fistula Rates- Comparison between older and recent studies ........ 28	 Figure 3-1 Combined fistula rates in patients with cleft lip and palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital ........................... 63	Figure 3-2 Fistula incidence rates in patients with unilateral cleft lip and palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital ......... 64	Figure 3-3 Fistula incidence rates in patients with bilateral cleft lip and palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital ......... 65	Figure 3- 4 Fistula incidence rates in patients with isolated cleft palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital ........................... 66	    xiii List of Abbreviations BC: British Columbia BCCH: British Columbia’s Children’s Hospital BCLP: Bilateral Cleft Lip and Palate CONSORT Checklist: Consolidated Standards of Reporting Trials Checklist ICP: Isolated Cleft Palate STROBE Checklist: Strengthening The Reporting of Observational Studies in Epidemiology Checklist UCLP: Unilateral Cleft Lip and Palate VPI: Velopharyngeal Insufficiency               xiv Acknowledgements My sincere and everlasting gratitude goes to my research supervisor, Dr. Jolanta Aleksejuniene, whose vision has guided me since the day we met. She has believed in me and encouraged me through every step of this long journey. Without her support and guidance, I would not be where I am now. I could not have imagined having a better mentor for my PhD study.   I was fortunate enough to have two supervisors and I would like to express my gratitude to my other supervisor, Dr. Edwin Yen for giving me the freedom to work my own way while providing me with his knowledge and guidance whenever I needed it.  I would also like to thank Dr. Angelina Loo, as a member of my committee, her assistance and input was invaluable in this project becoming a reality. She was instrumental in helping me gain access to British Columbia’s Children’s Hospital’s Cleft Center. Her dedication and level of commitment to cleft research is legendary. A special thanks goes to the cleft team at BC children’s hospital especially Sandra Robertson and Sheryl Palm for their help and support. They both made my days brighter throughout the time I spent collecting data at the hospital.      xv Dedication I dedicate this thesis to my mother, my father and my brother Nima, for their continuous support and encouragement throughout my many years of university education. Your love and support is the motivation that kept me going all these years.  I would also like to dedicate this thesis to my son Sam who has been so patient and understanding throughout my academic journey.1     Chapter 1: Introduction 1.1 Cleft Palate Deformity The cleft lip and palate congenital malformation is a common condition, which poses a large burden of care on the young patients and their caregivers. The World Health Organization reported the prevalence of cleft lip with or without cleft palate to be 10 in 10,000 births in the United States and worldwide and 12 in 10,000 births in Canada (IPDTOC, 2011). The management of cleft lip and palate patients is a long-term process that involves a multidisciplinary team, commonly consisting of an oral and maxillofacial surgeon, plastic surgeon, speech therapist, audiologist, pediatrician, orthodontist and social worker (Inman et al., 2005).   The successful surgical correction of the cleft palate deformity is still considered a challenge in reconstructive surgery (Parwaz et al., 2009). The Veau cleft lip and palate classification identifies four classes based on the location of the original defect: “I” soft cleft palate, “II” hard and soft cleft palate, “III” unilateral cleft lip or palate and “IV” bilateral cleft lip or palate (Cohen et al., 1991).  1.2 Techniques Used to Repair Cleft Palates  The ultimate goals of cleft repair are to close atypical communication between nasal and oral cavities, to restore the function of the levator veli palatini and to ensure that the palate has adequate length to restore complete velopharyngeal closure (Lin et al., 1999). A number of techniques have been used to repair cleft palates. The most common are: the 2    von Langenbeck palatoplasty technique, the Veau-Wardill Kilner technique, Furlow technique and the Bardach technique (Isik et al., 2011). Different techniques are commonly chosen for different type of defects, e.g. Veau or von Langenbeck flaps to repair the hard and soft palates and intravelar veloplasty or Furlow Z-plasty are used to repair soft palate clefts (Phua and de Chalain 2008).  Although multiple repair techniques have been employed, only a few comparative studies about their outcomes have been done. A relatively large study (N=346) by Amaratunga compared these two techniques; Langenbeck’s method and Wardill’s method, resulting in the former being associated with a lower fistula rate (Amaratunga 1988). Another retrospective study examined medical records over a 10 year time period and compared the Z-plasty technique to levator retro positioning and pharyngeal flap (Lin et al., 1999). Although both techniques were overall successful, the latter caused more serious postoperative complications (Lin et al., 1999). The study by Bekerecioglu et al. compared the two-flap and four-flap palatoplasties and did not find a difference in fistula rates (Bekerecioglu 2005).  The most comprehensive study on the prevention of post-palatoplasty fistulas, has been presented by Losee et al in 2008. This is a case series study of one surgeon’s work on 268 palatal procedures, such as primary cleft palate repair, oronasal fistula repair and secondary palatal repair for velopharyngeal insufficiency. This study relays a post palatoplasty fistula rate of 3%, which is one of the lowest rates ever reported and the lower rate of 0.8% is for symptomatic fistula rate occurring after the Furlow surgery (Losee et al., 2008). This study introduces a system to substantially reduce post 3    palatoplasty fistula by implementing relaxing incisions, total intravelar veloplasty, complete release of the tensor tendon, total dissection of the neurovascular bundle, and usage of acellular dermal matrix in complex cleft cases (Losee et al., 2008). Although this case series (study design) is not high on the hierarchy of evidence for studying risks, these approaches to lower fistula rates, once validated in other studies could be a step in the right direction. Despite many different techniques being used throughout the years only the few studies mentioned before were found and these studies only compared two techniques at a time. Consequently, recommending the optimal surgical method to repair cleft palate continues to be a dilemma (Lin et al., 1999).   1.3 Alveolar Bone Grafting  Alveolar bone grafting has been identified as a crucial step in the modern surgical algorithm for orofacial cleft management. The timing of the grafting still remains an important and controversial topic.  The commonly used terminology for alveolar bone grafting is as follows: • Primary: under 2 years old • Early secondary: 5-7 years old • Secondary: 7-11 years • Late secondary: older than 12 years 4    This classification is based on the child’s age and will signify the effect of bone grafting on maxillary growth and dental development (Eppley and Sadove 2000).  1.3.1 Primary Alveolar Bone Grafting The main goal in primary alveolar grafting is to avoid transverse maxillary collapse and occlusal distortions between the maxilla and mandible. Preferably this results in shorter orthodontic treatment in both mixed and permanent dentitions and reduces the need for future orthognathic surgery. The early eradication of the fistula stops nasal liquid-escape and helps facilitate good oral hygiene in early school years. In this method, an obturator is fabricated for all complete clefts (Eppley 1996, Dado 1993). 1.3.2 Secondary Alveolar Bone Grafting The main goal in secondary bone grafting is to create a uniform maxilla and make an osseous setting that can eventually support tooth eruption. This usually takes place at the mixed dentition stage (when the canine root is not completely formed) and it is accomplished in combination with orthodontic therapy (Cohen et al., 1993, Boyne and Sands 1972). The goals for secondary alveolar bone grafting are: 1) stabilizing the maxillary segments after orthodontic treatment, most importantly the mobile premaxilla in bilateral clefts, 2) promoting the prosthetic restoration by correcting the vestibular soft tissue relationships and, 3) closing the fistulas. A few studies also mentioned using osteoplasty to acquire functional bony tissue adjacent to the cleft, into which teeth could erupt without the need 5    for orthodontic treatment (Waite and Kersten 1980). 1.4 Post-operative Palatal Fistula The palatal fistula is an epithelialized opening in the repair between the mouth and nasal cavity, which has serious functional consequences (Schultz 1986). Therefore, avoidance of palatal fistulas in the treatment of cleft palates is critical (Lu et al., 2010). The reported incidence of fistula ranges from 4.7% to 60% (Phua and de Chalain 2008, LaRossa et al., 2004, Muzaffar et al., 2001).   Losee et al. in 2008 reported an incidence of palatal fistula as low as 0.8%. This paper quoted a range of incidence from 0 to 76% for fistula presentation in the literature. Fistulas are most common in the hard and soft palate and at the junction of the hard and soft palate (Amaratunga 1988). Fistulas are typically characterized according to their size, small: 1-2 mm, medium: 3-5 mm and large >5 mm. Additional classification schemes have described them as pinpoint, slit, oval, and total dehiscence (Schultz 1986).   The Pittsburgh Fistula Classification System introduced by Loose et al. in 2008 divides fistulas into seven different categories based on the location of the defect: Type I: fistulas at the uvula, or bifid uvulae Type II: fistula within the soft palate Type III: fistula at the junction of the soft and hard palates Type IV: fistula within the hard palate or junction of the primary and secondary palate 6    Type V: fistula at the incisive foramen Type VI: lingual-alveolar fistula Type VII: labial alveolar fistula  Zemann et al. in 2011 presented a different classification for oronasal fistulas. In this classification in addition to location, treatment methods are incorporated and it denotes the following categories: Class 1 defects: Fistula in alveolus, therefore requires bone coverage by soft tissue. Class 2 defects: Fistula in alveolar ridge and hard palate, therefore requires more soft tissue than Class 1 defect. Class 3 defects: Fistula in hard palate without passing junction to soft palate. Class 4 defects: Fistula includes parts of hard palate and soft palate. Class 5 defects: Rare and very wide clefts of hard palate and soft palate.  1.4.1 Patient Related Outcomes Most fistulas remain asymptomatic, but many patients may have the following complaints:  regurgitation into the nasal cavity, packing of food into the fistula, mucosal inflammation, malodor (Abyholm et al., 1979), nasal catarrh (Lehman et al., 1978), hearing loss (Schultz, 1986) and speech symptoms such as hypernasal resonance, audible nasal escape and weakness in pronouncing pressure consonants (Isberg and Henningsson 1987, Jackson et al. 1976). Fistulas usually have an adverse effect on patients’ speech, oral hygiene, and even mental health (Schultz, 1986). Normally, the acquisition of speech 7    is a multi-stage process (Wyatt et al., 1996). Around 3% to 25% of children with cleft lip and palate will develop normal speech after primary surgery, whereas others may require many interventions throughout childhood and adolescence (Dalston 1990). The important considerations involved in the treatment of cleft palate are to achieve normal speech without increasing maxillofacial growth disturbances and to minimize hearing loss and middle ear complications (Parwaz et al., 2009). Palatal fistula is evident shortly after palatoplasty and, depending on the size of the defect, it may influence velopharyngeal competence and speech (Sullivan et al., 2009). In contrast to fistula, the functional outcome of palatoplasty is not evident until the infant is older (Sullivan et al., 2009).   Velopharyngeal insufficiency (VPI), the audible sign of a nonfunctional palate, is unsuccessful velopharyngeal sphincter closure and is defined by hypernasal resonance and decreased intraoral pressure for pressure-dependent consonants during speech (Sullivan et al., 2009). The reported frequency of VPI is 5% to 30% (LaRossa et al., 2004, Bearn et al., 2001, Inman et al., 2005).  1.4.2 Factors Associated with Fistula Occurrence Formation of postoperative dehiscence or fistula has been proposed to be dependent upon a number of factors. Timing of the repair and gender are amongst the most common determinants mentioned in relation to fistula formation (Parwaz et al., 2009). Size of the defect matters, with clefts of the hard palate, soft palate and bilateral clefts having an increased probability of developing a fistula (Wilhelmi et al., 2001). In other studies 8    presentation of postoperative fistula has been linked to the width of the cleft, deficiency of the palate segments, misplacement and distortion of the cleft segment (Boyne, 1970).   A 2006 study related the increased probability of fistula formation to increased defect size such as bilateral cleft palate and complete cleft palate defects (Cole et al., 2006). Most experts are in agreement that the extent and magnitude of the preexisting cleft are the strongest predictors for postoperative oronasal fistula development. Patients with a Veau Type III or IV cleft have a significantly higher incidence of postoperative fistulas when compared with patients that have a Veau Type I or II cleft (Muzaffar et al., 2001; Cohen et al., 1991; Helling et al., 2006).   Width of the cleft palate in particular has a strong bearing on the occurrence of postoperative palatal fistula formation. Cleft width of 10 mm or more has been identified as a risk for fistula formation (Wilhelmi et al., 2001; Helling et al. 2006; Bresnick et al., 2003; Parwaz et al., 2009).  The study by Shultz 1989 found that fistula formation was related to the relative width of the palate when measured between the tuberosities and the width of the cleft when measured between the tuberosities (Elbel, 1985). They concluded that when this ratio was higher than 30 the probability for fistula formation became eight times stronger (Shultz, 1989). A 2009 study by Parwaz et al. also found that the preoperative cleft width of ≥15 9    mm and a ratio of cleft width to the sum of the palatal shelves’ width of ≥0.48 were significant predictors of fistula development (Parwaz et al., 2009).  Surgeon’s experience and type of surgical procedures have also been associated with fistula presentation (Muzaffar et al., 2001; Cohen et al., 1991; Bekerecioglu et al., 2005; Bindingnavele et al., 2008; Mak et al., 2006). Bearn et al.  examined surgeon’s experience and its relation to cleft palate outcome by comparing low-volume surgeons with high-volume surgeons. They found that high-volume surgeons have significantly lower fistula and hypernasality incidences after palatoplasty compared to low-volume surgeons (Bearn et al., 2001).  Other potential fistula-related risk determinants were the timing of the repair and accuracy of the surgical performance (Parwaz et al., 2009; Murthy et al., 2009, Salyer et al., 2006). It has been reported that early dehiscence and fistulas are primarily caused by errors in technique such as inadequate mobilization, closure under tension, injury at re-intubation, poor handling of tissues, failure to achieve a layered closure, post-operative bleeding or infection (Campbell, 1962).  A number of studies have mentioned excessive tension along the repair, necrosis of the flap, upper respiratory infection, formation of a hematoma and type of palatoplasty as potential risk determinants of fistula occurrence (Muzaffar et al., 2001; Amaratunga 1988, Musgrave and Bremner 1960). Consumption of hard food soon after surgery and manipulation of the surgical site by the patient have also been related to early wound failure (Kent and Martin, 2009).  10    1.4.3 Recurrence of Fistulas Currently there are many techniques for the repair of palatal fistulas; however the occurrence rate is still high ranging from 0% to 76% (Wilhelmi et al., 2001; Schultz 1986; Phua and de Chalain 2008; Sullivan et al., 2009; Rohrich et al., 1996; Nguyen and Sullivan 1993; Losee et al., 2008).     In addition to the mechanical consequences of fistula, the presence of a fistula often reflects a larger zone of scarring and unstable tissue along a tense palatal closure (Murthy et al., 2009). The poor tissue quality in this zone contributes to frequent recurrence after fistula repair with local tissue rearrangement (Lehman et al., 1978). Recurrent palatal fistulas cause challenges and dissatisfaction for both patients and surgeons (Schwabegger et al., 2004). In addition, recurrence rates after secondary fistula repair have been reported to be as high as 37% to 100% (Schultz 1986; Rohrich et al., 1996; Thaller 1995).   Poor blood supply, tissue paucity, scar adjacent mucosa and early wound contraction have been identified as reasons for fistulas recurrence (Jeffery et al., 2000).  The challenge of recurrent fistula is further aggravated by the paucity of local flaps available to use for tertiary repair (Murthy et al., 2009).      11    1.5 Study Rationale   Inconsistent findings were found in previous studies. For example, some studies reported that surgeon’s experience is a factor in the lower occurrence rate of fistula (Cohen et al., 1991;Murthy et al., 2009; Salyer et al., 2006), while Muzaffar et al. did not find such an association (Muzaffar et al., 2001). The lack of association in the Muzaffar et al. study can be explained to some extent, by the characteristics of their study design. The challenge with this study is the relatively small number of fistulas (N=8) and large number of surgeons (N=5), which means the study did not have sufficient power to show a significant association, even if such association in fact existed. The common limitation in cleft palate studies is small sample size (Elbel 1985; Abdel-Aziz et al., 2008; Ashtiani et al., 2011; Abdel-Aziz et al., 2012; Helling et al., 2006). Consequently, small sample size does not allow a comprehensive study of multiple determinants related to fistula occurrence. Possibly, this is one of the reasons studies comparing multiple techniques could not be found. Moreover, a substantial variation of outcomes exists, that can be due to lack of standardization, which in turn makes it difficult to interpret or directly compare evidence from different studies (Trost 1981).   The type of cleft repair, accurate surgical performance and surgeon’s experience have been identified as critical factors for achieving favorable outcomes in reducing fistula rates (Murthy et al., 2009; Salyer et al., 2006). Other important considerations are how patient-related outcomes are resolved after the completion of surgeries and how aftercare contributes to successful treatment. These questions can only be answered by conducting 12    a large study in a population where cleft palate occurrence is relatively high in which multiple determinants can be examined in a single study.   Even though the quality of speech is still the most important measure of success in palatoplasty, postoperative fistulas remain a significant challenge. Fistulas may be clinically significant when they lead to nasal air escape, speech distortion, hearing loss, or regurgitation of fluid and food. They may also cause velopharyngeal insufficiency, complicating speech development and food intake. Most importantly, fistulas are difficult to repair conclusively. The cleft palate literature surrounding fistula development is difficult to interpret due to vague definitions and the lack of standardized language addressing fistula location and its clinical significance (Losee et al., 2008).   Another important fact is that the First Nations population in British Columbia (BC), Canada at nearly 3 per 1000 births, has the highest prevalence of cleft lip and palate in the world (Lowry et al., 1989). In addition, the BC cleft lip and palate population data needs to be updated, since the latest review only covers the 1952-1986 period (Lowry et al., 1986). Based on considerations discussed above, studying the Canadian population provides a unique opportunity to comprehensively explore multiple factors potentially contributing to fistulas occurrence, both retrospectively and prospectively.      13    1.6 Research Question The present study focused on comprehensively examining palatal fistula and its related determinants.   1.6.1 Specific aims Project 1 (Chapter 2): To assess the level of available evidence regarding fistula occurrence in cleft lip and palate patients, evaluate the quality of original studies, and summarize all available evidence.  Project 2a (Chapter 3): To evaluate the incidence of post-operative palatal fistula in BC through a retrospective chart audit of cleft lip and palate patients treated at BC Children’s Hospital.   Project 2b (Chapter 3): To examine determinants related to the occurrence of palatal fistulas such as cleft type, cleft size, operator’s skill, timing of surgery, surgery technique, number of previous surgeries, age of patient and after care.  Project 3a (Chapter 4): To determine the advantages and limitations of the current clinical protocols for treating cleft lip and palate patients in relation to fistula occurrence.  Project 3b (Chapter 4): To design an all-encompassing standardized protocol for the follow-up of cleft lip and palate patients.    14    Chapter 2:  2.1 Introduction The cleft lip and palate congenital facial malformation is a rather common condition (e.g. in US 1 in 600 births) (Campbell et al., 2010). Research about the management of such patients has received more consideration in recent decades (Campbell et al., 2010). Fistula presence is frequently encountered after the surgical repair of a cleft lip and palate deformity (Hardwicke et al., 2014) and symptomatic fistulas may need other surgical repairs that pose an additional burden to young patients and their caregivers (Gowda et al., 2013). After primary repair a wide range of fistula occurrence rates have been reported (Lithovius et al., 2014).  In order to better understand the variation in the rates of fistula occurrence as well as what risk determinants are associated with a higher rate of fistula occurrence, a comprehensive analytical review of available evidence is necessary. The few available systematic reviews focused on some specific aspects related to the cleft lip and palate patients (Hardwicke et al., 2014; Gilleard et al., 2014; Price et al., 2016; Maarse et al., 2012). To the best of our knowledge, an all-encompassing comprehensive review broadly mapping not only the available evidence but also assessing the overall quality of evidence, while identifying limitations of the current research, is not available.   Prior to performing a thorough all-inclusive review, it is important to consider different types of reviews (secondary sources of evidence) that aim to produce a knowledge 15    synthesis of available original studies (primary sources of evidence). Three types of reviews: narrative reviews, systematic reviews and scoping reviews can be found in the scientific literature that provide an overview of what is known and agreed upon in a specific field of research.  Similarities and differences between these three types of reviews need to be considered. Systematic reviews and scoping reviews perform a systematic search of the primary sources of evidence prior to conducting their reports of knowledge synthesis, while narrative reviews do not employ such a strategy. Consequently, due to a mainly pre-selective and potentially more subjective nature inherent to narrative reviews clinicians should not rely on them as a source of evidence to support their decisions.   Conducting systematic reviews has been a common approach for synthesizing primary evidence, while scoping reviews have only become popular in more recent years (Daudt et al., 2013). Although, both systematic and scoping reviews search systematically in an attempt to identify all available sources of evidence, there are some substantial differences between these two strategies. First, systematic reviews most commonly focus on one specific research question. Second, systematic reviews apply standardized inclusion/exclusion criteria and preselect studies based on their quality for the subsequent knowledge synthesis. On the other hand, scoping reviews tend to address broader topics (several research questions) and have less limiting inclusion criteria for studies used in the knowledge synthesis (Arksey and  O'Malley 2005). Thus, the main aim of systematic reviews is to obtain a valid answer to a specific research question while scoping reviews 16    aim to broadly map the available evidence (Armstrong et al, 2011; Colquhoun et al., 2014).   Another key difference between the two is that systematic reviews provide knowledge synthesis using a reduced number of quality studies, while scoping reviews tend to seek several answers employing the information from a wider range of studies, the quality of which is usually not assessed (Arksey and O'Malley 2005).   It is important to acknowledge that both systematic and scoping reviews have their pros and cons. The main advantage of systematic reviews is that they produce the highest level of evidence to answer a specific question given that the studies used for research synthesis are of high quality, but systematic reviews frequently conclude that the available evidence is inconclusive (Smail-Faugeron et al., 2014). This inconclusive evidence resulting from systematic reviews clearly creates a dilemma for clinicians who need to make their everyday decisions based on the best available evidence that may be non-existing. When the evidence regarding different patient care related aspects, acquired from systematic reviews is either non-existing or insufficient scoping reviews that require less preparation time can be a useful alternative strategy for the systematic overview of available evidence and for assisting clinicians in their everyday treatment-related decisions.   17    A scoping review is a strategy for knowledge synthesis that incorporates different study designs and comprehensively synthesizes information from primary sources of evidence with the goal to inform clinical practices, programs and policy makers. It can also provide direction for future research (Colquhoun et al., 2014; Arksey and O'Malley 2005).   However, the main limitation of scoping reviews is that they do not apply a quality assessment of primary sources of evidence, this limitation, can be addressed by incorporating some guiding principles designed for systematic reviews into protocols of scoping reviews. Therefore, for the present study we chose to combine some principles from both systematic and scoping reviews to guide our broad overview of the evidence published in peer-reviewed sources about palatal fistula occurrence in cleft lip and palate patients. A cleft palatal fistula is a failure of healing or breakdown in the primary or secondary repair of the palate (Lu et al., 2010).  The aims of the present systematic scoping review were: 1) to assess the level of available evidence about fistula occurrence in cleft lip and palate patients 2) to identify main research areas in original studies 3) to evaluate the quality of evidence and 4) to perform knowledge synthesis of this evidence.     18    2.2 Methods  Designing a Protocol for the Systematic Scoping Review For the development of such a protocol we used some guiding principles for systematic reviews as outlined by the PRISMA 2009 checklist (Preferred Reporting Items for Systematic reviews and Meta-Analyses) (Moher et al., 2009) and followed the framework recommended for scoping reviews (Colquhoun et al., 2014). Given that the main scope of the present work was systematic and broad overview of all evidence, we chose a more inclusive approach to search for publications and for the extraction of relevant information from both primary and secondary sources of evidence.  The protocol for our systematic scoping review consisted of three phases.  Preparation phase consisted of two steps:  systematic data search and extraction of relevant evidence.  Assessment phase consisted of three steps: Assessment of levels of evidence including both primary sources of evidence (original studies) and secondary sources of evidence (reviews synthesizing information from original studies), identification of main research areas in original studies and quality assessment of original studies. Knowledge synthesis phase consisted of three steps: examination of findings from surgery studies, examination of findings from risk studies and analyses of summary data. For the details of each phase and its steps, refer to the protocol for the systematic scoping review as presented below.     19    2.2.1 Preparation Phase An inclusive extraction of peer-reviewed primary and secondary sources of evidence employing main and additional searches was performed by two independent researchers and consensus was achieved either by discussion or by inviting a third examiner. Given that the goal of the present systematic scoping review was to identify all available evidence in the topic of interest, we posed a broad search question: “What evidence is available about fistula and what are the risk determinants of fistula in cleft lip and palate patients?” Two independent researchers conducted the systematic search. In cases of disagreement, the consensus was reached through discussion, or engaging a third party when necessary.  For the main search, the following five electronic databases were searched: the Cochrane Database of Systematic Reviews, MEDLINE, Web of Knowledge, Web of Science and EMBASE. To maximize our search, we used only generic terms as both key and MESH terms: [“Cleft Palate” OR “Cleft Lip”] AND “Fistula”].  There was no limit to the year of publication. For the additional search, we hand-searched the reference lists of main papers and the Grey Literature. The summary results of the combined search are presented in a flow chart in Figure 2-1. This combined search produced a total of 1625 information sources, of which 724 were duplicates.  For the extraction of all relevant peer-reviewed sources of evidence we applied a two-step assessment procedure as illustrated in Figure 2-1. The extraction of relevant papers was performed by two independent researchers and consensus was achieved by 20    discussion or inviting a third examiner. A total of 901 sources of information were assessed for relevance employing the inclusion/exclusion criteria as outlined in Table 2-1. First the titles and abstracts were screened in order to exclude the non-human studies, non-English reports and studies without a full text. Second, after scanning the full papers, we excluded original studies where palatal fistula wasn’t the scope of the paper, where fistula rates were not reported and also non-peer reviewed sources such as letters, commentaries and summaries. This two-step assessment for relevance identified a total of 127 sources of evidence, consisting of both primary sources of evidence (reports about original studies) and secondary sources of evidence (reviews summarizing information from original studies).     21     Figure 2- 1 Flow Chart: data Search, extraction, selection, assessments and analyses        Tiles	&	abstracts	assessed	for	Relevance	(N=901)	Excluded	(N=	739)		Non-human,	Non-English	Full	Reports	not	available	Full	text	arFcles	assessed	for	Relevance		(N=	162)	Assessment		for	the	Levels	of	Evidence		(N=127)	Risk		Studies	N=	27	Excluded	(N=35)	LeNers,	Commentaries,	Summaries,		Not	reported	fistula	rates,			N=4	(2	SystemaFc	Reviews	)			(2	NarraFve	Reviews)		Surgery	Studies	N=	50	Titles	checked	for	Duplicates	(N=1625)	MAIN	SEARCH:		EMBASE	(N=732),	Medline	(N=624),	Web	of	Knowledge		(N=172),	Web	of	Science	(N=81).										ADDITIONAL	SEARCH:	Grey	Literature	&	Hand	Search	(N=16).	Small	Studies		(N<30	subjects)	N=	46	Quality	Assessment	&			ComparaFve	Analyses		(N=77)	Excluded	(N=724)	Duplicates		22    Table 2- 1 Inclusion and exclusion criteria employed for the selection of relevant studies Inclusion Criteria Exclusion Criteria Clinical evidence from peer-reviewed sources Evidence from not peer-reviewed sources Human studies in which repair of cleft lip and palate was performed.  Non-human studies  Fistula studied as a primary and/or secondary outcome^ Studies about cleft lip and palate patients in which fistula occurrence was not studied.  Primary sources of evidence: all study designs.  Secondary sources of evidence: systematic and narrative reviews.   Secondary sources of evidence: letters, commentaries and short summaries. Full reports available in English  Full reports not available or not in English Fistula rates reported (original studies) Fistula rates not reported (original studies) 23    ^Primary outcome- fistula is the primary focus and secondary outcome- fistula is the secondary focus of the study.   2.2.2 Assessment Phase This assessment was based on study designs and in accordance with the Hierarchy of Evidence (Twells 2015). For the primary sources of evidence, the study designs were defined as follows: “case report(s)” singular case reports or small studies (N<30 subjects), “case series” in which a scientific report presented information about 30 patients or more that were treated by one surgeon, “a retrospective cohort study” a retrospective audit of medical records of cleft lip and palate patients treated by multiple surgeons, “a prospective cohort study” a prospective follow-up study of at least 30 patients treated by ≥2 surgeons, “a non-randomized controlled trial” a study of ≥ 30 patients in which at least two interventions were compared but the process of allocation into groups for surgeries was not randomized, and “a randomized controlled trial” a surgery study or a risk study where at least two surgeries or two risks were associated with  fistula and the process of allocation into groups was randomized.   The assessment of secondary sources for the level of evidence was based on how the secondary sources of evidence identified primary sources of evidence and how they used this information in their scientific presentation. This way, a review was defined as “a narrative review” if an overview of primary evidence was not based on systematic extraction of all available evidence and we considered such reviews as expert opinions 24    (lower level of evidence) because guidelines for the systematic search and quality appraisal criteria were not followed. A review was noted as “a systematic review” if researchers performed an overview of primary evidence based on original studies extracted through a systematic search and knowledge synthesis was based on high quality studies. By evaluating all original studies, main focuses of research regarding fistula, its repair and its related factors in cleft lip and palate patients was identified.   Two independent researchers separately performed the quality assessment for each of the main research areas.  Consensus regarding the quality was achieved through discussion. The quality assessments were performed employing the adapted quality checklists that were considered most relevant for the two types of studies we identified. For these assessments, we chose to employ and adapt the CONSORT and STROBE checklists. In addition, we utilized the internal and external validity scoring systems. The latter we specifically designed considering the context of evidence we aimed to evaluate.   2.2.3 Knowledge Synthesis Phase  The goal of this phase was to summarize the main findings from both primary and secondary sources and to perform different analyses related to fistula occurrence, which we defined as the main outcome of interest. For knowledge synthesis of original studies we only used studies in which the sample size was ≥30 subjects. The knowledge synthesis phase included three steps: examination and description of findings extracted 25    from surgery studies, examination and description of findings extracted from risk studies and analyses of fistula rates for which fistula rates from both surgery studies and risk studies were combined to study the fistula rates in relation to publication date and the quality of scientific reporting. In these analyses, fistula rates were compared between the older studies (>10 years) and the more recent studies (<10 years) and also between the higher quality and lower quality studies. The SPSS Version 21.0 software was used for these comparisons and means ± SD of fistula rates among study groups were compared employing an independent sample t test, setting the threshold for statistical significance at P<0.05.  2.3 Results 2.3.1 Assessing the levels of available evidence about fistula in cleft lip and palate patients  The extracted sources of information were assessed in terms of levels of evidence in view of the fact that the highest levels of secondary sources of evidence are acquired from systematic reviews (Ng and Peh 2010) and the lowest levels of secondary sources of evidence are expert opinions commonly presented as narrative reviews, while the level of evidence of primary sources was based on study design. Subsequently the Hierarchy of Evidence comprising both primary and secondary sources of evidence was constructed (Figure 2-2).   26       Figure 2- 2 Hierarchy of Evidence- Fistula Occurrence in Cleft Lip & Palate patients   This Hierarchy of Evidence indicated that a total of 123 original studies were primary sources of evidence, and that there were four secondary sources of evidence, of which two were systematic reviews and two were narrative reviews (Figure 2-3). The overall level of evidence of the primary sources was relatively low as the field was dominated by case reports or small studies (46 studies) in which the sample size was below 30 subjects, followed by retrospective cohort studies (42 studies) and case series (25 studies).    The highest level of the secondary sources of evidence was represented by the two systematic reviews (Hardwicke et al., 2014; Timbang et al., 2014). One of these systematic reviews specifically focused on speech outcomes and fistula rates by Systematic Reviews*                        N=2 Randomized Controlled Trials          N=5  Non-Randomized Controlled Trials  N=2  Prospective Cohort Studies             N=3 Retrospective Cohort Studies          N=42 Case Series   (N>30 patients)          N=25 Small Studies  (N<30 patients)         N=46 Narrative Reviews*                          N=2 *  Secondary Source of Evidence	    Primary Source of Evidence 27    comparing two different surgery techniques and found that the higher failure rates were associated with the straight-line intravelar veloplasty (17%) as compared to Furlow double-opposing Z-plasty (10%) (Timbang et al., 2014). The other systematic review reported and analyzed the global incidence rates of fistula in cleft lip and palate patients (Hardwicke et al., 2014).           28      Figure 2- 3. Reported Fistula Rates- Comparison between older and recent studies   2.3.2 Identification of main research areas  Two main areas were identified among primary sources of evidence. One research area focused on surgeries used to repair cleft lip and palate defects (surgery studies) and the other research area focused on examining different risk determinants that could be associated with fistula occurrence in cleft lip and palate patients (risk studies). There were more surgery studies (N=50) than risk studies (N=27).    29    2.3.3 Assessment of the quality of evidence in main research areas based on original studies  Given that there were two main areas of research, we chose the CONSORT (Consolidated Standards of Reporting Trials) checklist (Lee et al., 2014) and adapted it to assess the quality of surgery studies and the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) (Vandenbroucke et al., 2014) checklist which we adapted to assess the quality of risk studies examining potential fistula related risk determinants. To enable statistical comparisons we needed to have an equal number of quality assessing criteria for both types of studies. The CONSORT checklist needed more adjustment than the STROBE checklist since only a small number of the surgery studies (interventions) were randomized controlled clinical trials. After our adjustments, the adapted CONSORT checklist contained a total of 18 items (Table 2-2) and similarly the adapted STROBE checklist also comprised a total of 18 items (Table 2-3). Both, the adapted CONSORT and STROBE checklists were used for the general assessment of the quality of scientific reporting.   Concomitantly, we considered that assessing some important aspects of internal validity as well as external validity were of key importance. For such validity scoring, we used a total of 12 items, four of which were related to the assessment of internal validity and eight were used to evaluate different aspects of external validity (Table 2-4).   30     Table 2- 2 Quality assessment of cleft lip and palate repair studies (Surgery studies: N≥30) Section/Topic No Checklist item# N * (% of all) Title and abstract 1 Informative title  43 (86.0%)      2 Structured abstract 29 (58.0%) Introduction Rationale Objectives 3 Scientific background and explanation of rationale 27 (54.0%) 4 Specific objectives or hypotheses  28 (56.0%) Methods Control 5 If controlled study, described what served as a control  20 (40.0%) Participants 6 Eligibility criteria for participants described 41 (82.0%) Settings 7 Settings and locations where the data were collected 40 (80.0%) Interventions 8 Interventions (surgeries) presented with details  48 (96.0%) Outcomes 9 Pre-specified outcome measures 36 (72.0%) Results Baseline data Follow-up 10 11 Baseline characteristics presented  The length of follow-up presented 40 (80.0%) 43 (86.0%) Outcomes 12 Detailed results for primary and/or secondary outcomes^ 43 (86.0%) Statistics  13 14 Basic statistical analyses presented  Subgroup analyses  16 (32.0%) 15 (30.0%) 31    Complications 15 Harms or unintended effects due to surgeries presented 22 (44.0%) Discussion Interpretation 16 Interpretation consistent with results 44 (88.0%) Generalizability Limitations 17 18 Findings interpreted in the context of available evidence Study limitations discussed 44 (88.0%)  12 (24.0%)  #Adapted from the upgraded CONSORT checklist 19 * Numbers reflect studies that received a “Yes” for an item  ^Primary outcome- fistula is the primary focus and secondary outcome- fistula is the secondary focus of the study.       32    Table 2- 3Table 2-3. Quality assessment of studies examining fistula related risk determinants in cleft lip & palate patients (Risk Studies: N≥30)  Section/Topic No Checklist item # N* (% of studies) Title  Abstract 1 Informative title  24 (88.8%)      2 Structured abstract  13 (48.1%) Introduction Rationale Objectives 3 Scientific background and explanation of rationale 24 (88.8%) 4 Specific objectives or hypotheses  25 (92.5%) Methods Sample size 5 Necessary sample size calculated a priori   1 (3.7%) Participants 6 Eligibility criteria for participants described 26 (96.2%) Settings 7 Setting and location where the data was collected 22 (81.4%) Follow-up 8 The length of the follow-up reported 24 (88.8%) Variables 9 Measurements of risks and outcomes described in detail  27 (100%) Results Baseline data 10 Baseline characteristics presented 25 (92.5%) Variables 11 Detailed results for risk determinants 26 (96.2%) Outcomes 12 Detailed results for outcomes (fistula occurrence) 27 (100%) Statistics  13 14 Basic statistical analyses presented (univariate analyses) Analyses for risk determinants (bivariate analyses) 26 (96.2%) 24 (88.8%) 33     15 Analyses for multiple risk determinants (multivariate)   3 (11.1%) Discussion Interpretation 16 Interpretation consistent with results 27 (100%) Generalizability Limitations 17 18 Findings interpreted in the context of available evidence Authors discussed limitations of their own study  25 (92.5%)  13 (48.1%) #Adapted from the STROBE quality assessment checklist 20 * Numbers reflect studies that received a “Yes” for an item    34    Table 2-4 Internal and External Validity Assessments (all surgery & risk studies included)  Section No Checklist items   N (% of a total studies) INTERNAL VALIDITY                                                                             Methods  Results  Surgery studies     Risk studies 1 Blinded/Independent assessments  12 (24.0%)          3 (11.1%) 2 Pre-specified measurements*   33 (64.0%)         26 (96.2%) 3 Presentation of outcomes in detail# 39 (78.0%)        25 (92.5%)  4 Missing data presented/analysed 17 (34.0%)        26 (96.2%) EXTERNAL VALIDITY Sample size Recruitment              Setting            Length  Controlled study  Strong design   Multiple surgeons Follow-up 5 6 7 8     9      10     11 12 ≥ 100 patients All patients included Large centres or hospitals  Length of recruitment over a year ≥2 surgeries compared (surgery studies)  ≥2 risks controlled (risk studies)  Subjects randomly allocated to surgeries ^ Prospective cohort study^  Multiple surgeons   Patients followed-up ≥ three months 21 (42.0%)         19 (70.3%) 28 (56.0%)         20 (74.0%)   38 (76.0%)         22 (81.4%) 42 (84.0%)         23 (85.1%) 29 (58.0%)                                         3 (11.1%)    3 (6.0 %)                                       13 (48.1%) 25 (50.0%)          16 (59.2%) 33 (66.0%)          19 (70.3%) 35    * In surgery studies the surgery is explained in detail and in risk studies the risk measurements are explained in detail. # Fistula assessments explained in detail. ^ In surgery studies, subjects were randomly allocated into intervention groups (surgeries) ^ In risk studies, the risk determinants were studied in a prospective cohort study design.   Reviewing the quality assessment of surgery studies presented in Table 2-2, we can see that the overall quality of scientific reporting in surgery studies was low, for some criteria in particular. The lowest quality score was related to researchers failing to discuss the limitations of their own studies, while the main focus in these scientific reports (96% of all surgery studies) was attributed to describing the surgeries in great detail. It is important to note that a substantial proportion of surgery studies did not have the description of the study settings and the location where the study was conducted (20% of all surgery studies). Another important limitation was that half of the surgery studies published in peer-reviewed journals did not report aims or hypotheses (44% of all studies).     The quality assessment of scientific presentations of risk studies is presented in Table 2-3. The overall quality of studies examining the risk determinants of fistula was superior to the quality of the scientific presentations of surgery studies. Around 48% of risk studies and 24% of surgery studies discussed their own limitations and the majority of 36    risk studies (96%) performed at least some form of basic statistical analysis, while the corresponding proportion for the surgery studies was substantially lower (32%). Although expected, only a small proportion of the risk studies (11%) employed multivariate analyses for the joint analyses in which several potential risk determinants were jointly assessed for fistula occurrence in cleft lip and palate patients. The assessment of internal/external validity scoring for both types of studies is presented in Table 2-4. Assessment of internal validity was comprised of a total of four items. Low proportions of both types of studies (11% of risk studies and 24% of surgery studies) employed blinded measurements, i.e. it seems that data collection for the majority of scientific reports was either acquired by the surgeons who performed the surgeries themselves or by their colleagues. The overall internal validity of surgery studies was substantially lower than risk studies. Information about potentially missing data could only be found in a third of surgery studies (34% of surgery studies), while some form of information about missing data was found in the majority of risk studies (96% of risk studies).   In regards to external validity, the majority of both study types (>84%) with sample sizes ≥ 30 patients recruited their participants for a year or longer. The largest difference in external validity between the two types of studies related to the strength of the study design, whether or not the study was controlled and the sample size. Of all, 58% of surgery studies were controlled compared to 11% of risk studies and 48% of risk studies 37    had a strong design compared to 6% of surgery studies. The sample sizes in the surgery studies were substantially smaller than the sample sizes in the risk studies.     2.3.4 Knowledge Synthesis  The complete list of small studies is presented in Table 2-5. For the knowledge synthesis, only studies with a sample size of 30 patients or more were included. The surgery studies used for knowledge synthesis are presented in Table 2-6 and the risk studies are presented in Table 2-7. For the subsequent statistical comparisons surgery studies and risk studies were combined in order to associate fistula rates with publication dates and the overall quality of scientific reporting.  Table 2-5  Small studies: N< 30 patients Author/Year Reason for exclusion Fistula rates STUDIES EXCLUDED FROM QUALITY ASSESSMENTS Cruz de Castro, 2015  Small sample (N=1) 0% (secondary)   Harish, 2014  Small sample (N=1) None reported Charan Babu, 2009  Small sample (N=1) 0% (secondary) Penna, 2007  Small sample (N=1) 0% (secondary) Alkan, 2007  Small sample (N=1) 0% (secondary) Krimmel, 2005  Small sample (N=1) 0% (secondary) Yen, 2003  Small sample (N=1) 100% (secondary)  Al-Qattan, 2001 Small sample (N=1) 0% (secondary) 38    Author/Year Reason for exclusion Fistula rates STUDIES EXCLUDED FROM QUALITY ASSESSMENTS Bureau S. 2001 Small sample (N=10) None reported Hill, 1999  Small sample (N=1) 0% (secondary) Ninkovic, 1997  Small sample (N=2) None reported Barone, 1993  Small sample (N=1) 0% (secondary) Karling, 1993  Small sample (N=12) None reported De Mey, 1990  Small sample (N=1) 0% (secondary) Morikawa, 1987  Small sample (N=1) None reported Posnick, 1987  Small sample (N=2) 0% (secondary) Herbert, 1974  Small sample (N=1) 0% (secondary) Wallace, 1966  Small sample (N=3) 33% (secondary) Dayashankara, 2011 Small sample (N=24) 16% (primary) Abdali, 2014  Small sample (N=29) 21% (secondary) Fang, 2014  Small sample (N=22) 18% (secondary) Shetty, 2013  Small sample (N=11) 0% (secondary) Abdel-Aziz, 2012  Small sample (N=19) 0% (secondary)  Ashtiani, 2011  Small sample (N=20) 0% (secondary)  Celebiler, 2011  Small sample (N=10) 10% (primary) Ashtiani, 2011  Small sample (N=29) 0% (secondary) Jenq, 2011  Small sample (N=7) 29% (secondary) 39    Author/Year Reason for exclusion Fistula rates STUDIES EXCLUDED FROM QUALITY ASSESSMENTS Isik, 2011  Small sample (N=28) 8% (primary) Abdel-Aziz, 2010  Small sample (N=14) 0% (secondary) Sader, 2010  Small sample (N=10) 0% (secondary) Lahiri, 2007  Small sample (N=14) 25% (secondary) Cole, 2006  Small sample (N=5) 0% (secondary) Steele, 2006  Small sample (N=21) 17% (secondary)  Ashtiani, 2005  Small sample (N=22) 14% (Secondary)  Jeffery, 2000  Small sample (N=14) 21% (secondary) Honnebier, 2000  Small sample (N=7) 0% (secondary) Lin, 1999  Small sample (N=24) 12% (primary) Assuncao, 1993  Small sample (N=12) 8% (secondary)  Argamaso, 1990  Small sample (N=6) 16% (secondary) Kummer, 1989  Small sample (N=3) 0% (primary) Coghlan, 1989  Small sample (N=20) 25% (secondary) Watson, 1988   Small sample (N=13) 38% (secondary) Nakayama, 1987  Small sample (N=9) 22% (secondary) Pigott, 1984  Small sample (N=20) 15% (secondary)  Carreirao, 1980  Small sample (N=13) 0% (secondary) Berkman, 1978  Small sample (N=11) 9% (secondary) 40    Table 2-6 presents some key elements of surgery studies (N=50) while only including studies in which the sample size was ≥30 subjects. Most of these surgery studies were retrospective cohort studies.  There was a wide range of variation in the number of patients these studies used in their reports. Over half of the surgery studies (68%) had less than 100 subjects. In this body of evidence primary, secondary, tertiary and quaternary fistula rates could be found. One can see that a wide variation of fistula rates was reported in different surgery studies, particularly primary fistula rates, ranging from 0% to 40%. Another observation was that there was considerable heterogeneity regarding surgery techniques (a variety of different surgery techniques were described in the studies) that made any further quantitative comparisons among these studies unfeasible.  Table 2- 6 Cleft lip and palate related surgery studies that reported on N≥30 patients   Author, year (design)   N Surgery performed (PP- palatoplasty) Fistula rates Nadjmi, 2013 (RCT)  40 Modified Furlow PP 0% (primary) Abdel-Aziz, 2011 (RCT)  60 V-Y push back PP, Furlow PP 4% (primary) Richard, 2006 (NRCT)  37 For hard palate - Single layer Vomerine flap  For soft palate - medial von Lagenbeck incisions 34% (primary) Hassan, 2007(NRCT)  70 Wardill-Kilner PP, Kriens PP 14% (primary) Ferdous, 2010 (PCS)  43 One stage lip and palate repair with vomer 5% (primary) 41    Author, year (design)   N Surgery performed (PP- palatoplasty) Fistula rates flap, Two stage repair Basta, 2014 (RCS)  132 Primary modified Furlow PP 5% (primary) Kahraman, 2014 (RCS)  167 V-Y push back PP, Furlow PP, Rotation flap PP, Rotation bipedicular PP,  Rotation & Island flap PP  18% (primary) Mahajan, 2014 (RCS)  41 Tongue flap PP   0% (primary) Abdurrazaq, 2013 (RCS)  131 von Lagenbeck PP 30% (primary) Engelbrecht, 2013 (RCS)  31 Superiorly based vomer flap,  Circumferential dissection von Lagenbeck closure 5% (secondary) Buyu, 2012(RCS)  94 Surgery type not reported  5% (primary) Koudoumnakis, 2012 (RCS)  257 Two flap PP 7% (primary) Dong, 2012(RCS)  88 Furlow PP, Two flap PP  0% (primary) Murthy, 2011(RCS) 194 von Lagenbeck PP, Alveolar extension PP flap, Tongue flap PP 5% (primary) Losken, 2011(RCS)  126 Veau-Wardill-Kilner PP, Bardach two flap PP,  von Lagenbeck PP, Furlow PP  2% (primary) 42    Author, year (design)   N Surgery performed (PP- palatoplasty) Fistula rates Gupta, 2011(RCS)  77 Modified Furlow PP 3% (primary) Freda, 2010 (RCS)  117 Two and three layer closures 35% (secondary) 23% (tertiary) 9% (quaternary) Stewart, 2009 (RCS)  182 Modified von Lagenbeck PP 0% (primary) Phua, 2008 (RCS)  211 Veau PP, von Lagenbeck PP, Furlow PP 13% (primary) Smith, 2007(RCS)  641 Surgery type not reported 40% (primary) Xu, 2007 (RCS)  37 Square flap PP 0% (primary) Agrawal, 2006 (RCS)  678 Vomerine flap PP 3%  (primary) Inman, 2005 (RCS)  148 von Lagenbeck PP, Wardill-Kilner PP 5% (primary) Pigott, 2002 (RCS)  139  Cuthbert Veau PP, von Lagenbeck PP,  Medial Lagenbeck PP 11% (primary) Pulkkinen, 2001(RCS)  278 Veau-Wardill-Kilner V-Y pushback PP, Cronin modification PP, Shweckendiek modification PP 19% (primary) Becker, 2000 (RCS)  66 von Lagenbeck PP, Wardill PP 15% (primary) Contreras, 1989 (RCS)  177 Tongue and forehead flap PP 13% (primary)  5% (secondary)  Jackson, 1982 (RCS)  112 Veau PP 16% (primary) Hortis, 2014 (CS)  137 Bi /Unilateral von Langenbeck PP, 23% (primary) 43    Author, year (design)   N Surgery performed (PP- palatoplasty) Fistula rates Vomerplasty Winters, 2014 (CS)  70 Two flap PP & Furlow PP both with Alloderm 4% (primary) Tan, 2012 (CS)  34 von Lagenbeck PP with Z plasty 0% (primary) Abbas, 2011 (CS)  48 Modified von Lagenbeck PP 2% (primary) Hodges, 2010 (CS) 106 Sommerlad PP 8% (primary) Koh, 2009 (CS)  31 Two flap PP, Modified two flap PP 13% (primary) Losee, 2008 (CS)  268 Furlow PP,  Oronasal fistula repair (surgery type not specified) 1% (primary) 4% (secondary)  Abdel-Aziz, 2008 (CS)  33 Superior lip myomucosal flap 9% (secondary) Diah, 2007(CS) 64 Local flap PP, Two flap PP, von Lagenbeck PP, Furlow PP, Tongue flap PP 5% (primary) 20% (secondary) Helling, 2006 (CS)  31 Furlow PP 3% (primary) Ogata, 2006 (CS)  48 PP with marginal musculo-mucosal flap 6% (primary) Mak, 2006 (CS)  54 Furlow PP 6% (primary) Salyer, 2006 (CS)  382 Two flap PP 15% (primary) Bekerecioglu, 2005 (CS)  73 Two flap PP, Four flap PP 7% (primary) 44    Author, year (design)   N Surgery performed (PP- palatoplasty) Fistula rates Denny, 2005 (CS)  60 Type of surgery technique not mentioned 10% (primary) Sommerlad, 2003 (CS)  285 PP with Lagenbeck flaps 15% (primary Chait, 2002 (CS)  35 Modified two stage closure 6% (primary) Timmons, 2001 (CS)  54 Veau PP, Lagenbeck PP, medial Lagenbeck PP, Veau/Lagenbeck midline PP 4% (primary)  Wilhelmi, 2001 (CS)  119 Two flap PP 3% (primary) Akoz, 1995 (CS)  47 Wardill-Kilner V-Y PP with fascia lata homograft 8% (primary) Grotepass, 1990 (CS)  38 Triple layer flap PP 25% (secondary) Rintala, 1980 (CS)  71 Hinge flap PP, Bone graft, Rotation flap PP,  Island flap PP, Lingual flap PP 34% (secondary)     RCT Randomized Controlled Trial, NRCS Non-Randomized Controlled Trial, RCS Retrospective Cohort study, PCS Prospective Cohort study, CS Case Series.    Similar to surgery studies, the overview of risk studies in Table 2-7 revealed a substantial variation among these studies in relation to sample size. The risk studies reported primary and secondary fistula rates with the highest primary fistula rate of 78% (Mak et al., 2006). In a total of 27 risk studies, around 30 risk determinants were evaluated. The most frequently examined risk determinants were: age at surgery (17 studies), type of cleft (15 45    studies), surgery techniques (12 studies) and surgeon’s experience (14 studies). Due to the heterogeneous nature of the risk studies we could only perform some general comparisons that revealed that the most frequently studied risk determinants did not present consistent patterns across different studies, i.e. in some studies the risks associated with fistula were significant while in other studies the same risks were not statistically significant. For example, the relationship between fistula occurrence and age at surgery was non-significant in most risk studies (N=13 studies) while a few studies found it to be significant (N=4 studies).  There was similar inconsistency in regards to surgeon’s experience and fistula occurrence. The majority of studies (N=8 studies) found no significant association between surgeon’s experience and fistula occurrence while other studies (N=6 studies) found a significant association. Also the severity of the cleft was associated with higher fistula rates in three out of six studies and the width of the cleft was significantly associated with higher fistula rates in four out of five studies.     46        Table 2-7 Cleft lip and palate related risk studies that reported on N≥30 patients Author, Year (design) N Risk determinants Fistula rates  Williams, 2011 (RCT)  467 Gender, Cleft width*, Age at surgery,  Surgery technique*, Surgeon’s experience* 18% (primary) Kim, 2009 (RCT)  82 Type of feeding device 12% (primary) Jigjinni, 1993 (RCT)   46 Associated cleft of a lip, Length and width of cleft, Associated syndrome, Digit sucking,  Preoperative orthodontic treatment,  Age at surgery, Surgery technique, Arm splint  24% (primary)  Parwaz, 2009 (PCS)  31 Ratio of maximum cleft width to sum of width of palatal shelves*, Ratio of cleft width to the inter-tuberosity distance*, Posterior arch width*,  Surgery technique, Surgeon’s experience. 35% (primary) Rennie, 2009 (PCS) 103 Severity of cleft*, Staphylococcus Aureus, Upper respiratory infection before surgery*, Surgery technique 26% (primary) 47    Author, Year (design) N Risk determinants Fistula rates  Rossell-Perry, 2015(RCS)  680 Surgical mission* Mission: 25% (primary) Referral centre: 4% (primary) Lithovius, 2014(RCS)  136 Gender, Type of cleft*, Cleft severity, Age at surgery, Surgery technique   10% (primary) Sullivan, 2014 (RCS)   55 Gender, Type of cleft, Age at surgery* 9% (primary)  Rossell-Perry, 2014 (RCS)   152 Palatal Index*, Severity of cleft*, Tissue deficiency*  9% (primary) Stransky, 2013 (RCS)   184 Associated syndromes (Pierre Robin) 4% (primary)  Al-Nawas, 2013 (RCS)  94 Age at surgery, Leucocyte counts, Duration of surgery, Surgeon’s experience, Weight loss* 5% (primary) Jackson, 2013 (RCS)  869 Gender, Type of cleft*, Age at surgery,  Surgeon’s experience 5% (primary) 48    Author, Year (design) N Risk determinants Fistula rates  Doucet, 2013 (RCS)  40 Malek Protocol vs. Talmant Protocol*,  Age at surgery, Surgery technique 28% (primary)  Maine, 2012 (RCS)  128 Type of cleft*, Age at surgery, Weight at surgery, Poor oral health*, Surgeon’s experience. 56% (primary) Michelotti, 2012 (RCS) 120 Post-operative arm restraint,  Post-operative infection. 5% (primary) Lu, 2010 (RCS)  176 Gender, Type of cleft*, Age at surgery,  Surgeon’s experience* 8% (primary) Landheer, 2010 (RCS)  275 Gender, Type of cleft, Cleft width*,  Associated syndrome, Age at 2nd surgery*,  Surgery technique*, Surgeon's experience 21% (primary)   9% (secondary) Andersson, 2008 (RCS)  814 Gender, Type of cleft*, Severity of cleft *,  Age at surgery*, Surgeon's experience* 4% (primary) Bindingnavele, 2008 (RCS) 500 Gender, Type of cleft, Age at surgery,  Surgery technique* 5% (primary) Bresnick, 2003 (RCS)  560  Type of cleft, Associated syndromes*,  Treacher 49    Author, Year (design) N Risk determinants Fistula rates  Surgery technique, Surgeon's experience Collins Syndrome: 50% (primary) Other Syndromes:  9% (primary)  No Syndrome: 4%(primary) Muzaffar, 2001 (RCS)  103 Gender, Type of cleft*, Pre-surgical orthopaedics, Age at surgery, Surgery technique,  Surgeon’s experience, Palatal expansion 9% (primary) 33% (secondary) Emory, 1997 (RCS)  113 Gender, Type of cleft, Age at surgery*,  Surgery technique, Surgeon’s experience* 12% (primary) 9% (secondary) Cohen, 1991 (RCS)  129 Gender, Type of cleft*, Age at surgery,  Surgery technique*, Surgeon’s 23% (primary) 50    Author, Year (design) N Risk determinants Fistula rates  experience* 37% (secondary) Nakakita, 1990 (RCS)  42 Fistula size, Fistula location 69% (primary) Murthy, 2009 (CS)  332 Gender, Type of cleft, Age at surgery,  Surgeon's experience* 2% (primary)  Sullivan, 2009 (CS)  449 Type of cleft, Age at surgery, Surgeon's experience 3% (primary) Mak, 2006 (CS)  57 Gender, Body weight, Type of cleft*, Cleft severity, other congenital anomalies, Age at surgery, Duration of surgery*,  Hemoglobin levels, Blood loss 78% (primary)  RCT Randomized Controlled Trial, NRCS Non-Randomized Controlled Trial, RCS Retrospective Cohort study, PCS Prospective Cohort study, CS Case Series. * Risk Determinants significantly associated with fistula occurrence.   The following associations were studied: fistula rates were compared between the older studies (publication date over 10 years) and more recent studies (publication date less than 10 years) and between the higher quality and lower quality studies. The medium value of the total quality score either from the adapted CONSORT (for surgery studies) 51    or from the adapted STROBE checklist (for risk studies) was used to allocate studies in high quality or low quality groups of scientific reporting. The statistical analyses did not identify a statistically significant association between fistula rates and different types of studies, i.e. there were no statistically significant differences in fistula mean ±SD rates of older studies versus more recent studies or in studies with a higher quality of reporting versus the ones with a lower quality of scientific reporting (independent sample t test, P>0.05). We did not perform meta-analyses in the present systematic scoping review as such information is available in a recently published systematic review (Hardwicke et al., 2014).   2.4 Discussion The present systematic scoping review broadly evaluated the available evidence about fistula occurrence in cleft lip and palate patients. It also examined the level of available evidence by considering both primary and secondary sources, identified main directions in original research and assessed the quality of reporting in original studies.    Evidence Based Medicine is an integration of clinical proficiency with the best available evidence, while taking the patient’s expectations into consideration (Sackett et al., 2000). In order to make effective clinical decisions and provide patients with the best possible treatment, clinicians need to practice evidence-based medicine (Bolus 2015) and continuously upgrade their knowledge of the evidence from the best available sources in a time-efficient manner. Thus, clinicians will first look for evidence in systematic 52    reviews, which are commonly considered the highest level of evidence (Ng and Peh 2010). However, the systematic reviews attempting to synthesize knowledge commonly conclude that high quality primary sources of evidence (original studies) are scarce at best. Moreover, a rather frequent occurrence in systematic reviews is that their knowledge synthesis is based on a substantially reduced number of preselected studies.   An alternative to systematic reviews is to perform a scoping review that provides a ‘broad mapping of the available evidence’ (Levac et al., 2010). However, the main limitation of scoping reviews is that they do not assess the quality of studies used for the subsequent synthesis of knowledge (Rumrill et al., 2010).    The present systematic scoping review compensated for this limitation by including the quality assessments in the protocol.  We adjusted two commonly used quality assessment checklists (CONSORT, STROBE) in order to have less stringent criteria for evaluating studies in our field of interest mainly because there were only a few randomized controlled trials, which represent the highest level of primary evidence (Manchikanti et al., 2008), the "gold standard" by which clinical research is judged (Adeyemo et al., 2007). Despite the use of less stringent criteria for our quality assessments, we found that the overall quality of scientific reporting in both types of studies was low, particularly in reports about different surgeries related to the repair of cleft lip and palate defects. The sub-optimal quality of scientific reports was also reported in recent methodological reviews (Turner et al., 2013; Smith et al., 2015; Agha et al., 2016). 53    Although our systematic scoping review found more recent studies to be of higher quality when compared to older studies, the overall quality of scientific reports was unsatisfactory. It is important to consider the results of the recent systematic methodological review, which reports that the higher quality of scientific reporting was associated with journals adopting quality assessment checklists as a requirement for their authors (Plint et al., 2006). In the event that more editorial teams employ such guidelines an overall improvement of scientific reporting may be expected in the future.   A Hierarchy of Evidence is commonly used to assess the level of evidence of both primary and secondary sources of evidence on which clinical decisions are made (Guyatt et al., 2008). In this Hierarchy of Evidence, systematic reviews with meta-analyses (the secondary source of evidence) are often at the top (Adeyemo et al., 2007; Sinha et al., 2012). Our systematic scoping review identified two systematic reviews and they were each focused on one research question. One systematic review reported on global primary fistula occurrence rates in cleft lip and palate patients (Hardwicke et al., 2014). In the other systematic review the failure rates of two surgical techniques were compared and they found that the failure rate for the Furlow double-opposing Z-plasty (10%) was lower than the straight-line intravelar veloplasty (17%)(Timbang et al., 2014).  To assess primary sources of evidence, we extracted reports from multiple original studies in two main research areas, one related to surgical repair and the other to the study of potential risk determinants of fistula occurrence in cleft lip and palate patients. 54    To obtain the best primary evidence about treatments (e.g. surgeries), the Hierarchy of Evidence places good quality randomized controlled trials at the top of the evidence pyramid, while the study of prognostic and risk factors is best addressed with prospective cohort studies (Parfrey and Ravani 2015). It is important to emphasize that the present systematic scoping review only found a few randomized trials and a few prospective cohort studies while the majority of the research in this field is dominated by weaker study designs such as small studies with less than 30 patients, retrospective cohort studies that commonly have a substantial proportion of missing data and case series which are presentations of a single surgeon’s experience.   Our knowledge synthesis of this low quality primary evidence demonstrated a wide range of primary fistula occurrence in both types of studies. No significant difference was found in the fistula rates of older studies compared to more recent studies and no significant difference in fistula mean rates was noted between different quality studies. Multiple risk determinants were studied and age at surgery, surgeon’s experience, type and severity of cleft were the most frequently examined risk determinants. However, findings regarding different risk determinants and fistula occurrence were inconsistent.    Limitations of the present systematic scoping review are as follows: first, both types of the extracted original studies were very heterogeneous. Therefore, we could not perform quantitative subgroup analyses that could have potentially produced important knowledge, particularly about risk determinants of fistula occurrence in cleft lip and 55    palate patients.  Second, we needed to adjust both CONSORT and STROBE checklists for the quality evaluations. Due to this adjustment, the quality of reports in the field that we reviewed can’t be directly compared to the quality of reports in other medical fields.   2.5 Conclusions The field of fistula research focused mainly on surgeries and fistula related risk determinants. The available evidence was of low level and poor quality. A wide range of primary fistula rates was reported. Overall, fistula rates did not differ significantly when comparing older studies with more recent studies or high quality studies with low quality studies. No consistent pattern of significant association between fistula occurrence and any of the risk determinants examined in different studies could be detected.            56    Chapter 3: Time trends and determinants of fistula in cleft patients at BC Children’s Hospital, Canada. A Retrospective 18 Year Medical Chart Audit. 3.1 Introduction The WHO reported that the prevalence of cleft lip with or without cleft palate in the U.S. and worldwide is 10 in 10,000 births and 12 in 10,000 births in Canada (IPDTOC, 2011). For the First Nations population of British Columbia, Canada this rate is even higher, with nearly 3 per 1000 births (Lowry et al., 2009). The management of cleft lip and palate patients is a long-term process, which involves a multidisciplinary team (Inman et al., 2005).  A postoperative palatal fistula, an epithelialized opening in the repair between the oral cavity and the nasal cavity (Lu et al., 2010) is a common complication after the cleft palate surgery (Phua and de Chalain, 2008). Consequences of such fistula are potential regurgitation of food and fluid into the nasal cavity and air escape during speech, which results in hyper-nasality (Inman et al., 2005). Studies examining fistula-related risk determinants revealed that the most frequently studied risk determinants did not present with consistent patterns, i.e. in some studies the risks associated with fistula were significant while in other studies the same risks were not statistically significantly in relation to fistula occurrence (Lithovius et al., 2014; Williams et al., 2011; Landheer et al., 2010; Parwaz et al., 2009). 57     Globally, the occurrence of palatal fistula after palate repair varies greatly among different centers and is reported to range from 0 to 78 percent (Bardach et al.,1984; Senders and Sykes, 1995; Mak et al., 2006) whereas the recurrence rate of palatal fistulas (secondary, tertiary, etc.) reportedly approaches 65 percent (Shultz, 1986).  The few Canadian studies available did not examine time trends of fistula occurrence in the cleft lip and palate patients. A Canadian study by Mahoney et al. examined fistula rates and related factors, but this study only included one surgeon’s experience (Mahoney et al., 2013). The reason for the substantial variation in incidence rates among different centers is still unclear. Furthermore we are unaware of how Canadian fistula rates compare with the rest of the world.   Studying the time trends of fistula occurrence and fistula-related determinants can give us a better understanding about this rare condition and help us identify significant determinants associated with fistula occurrence. Thus, a comprehensive study carried out by independent researchers, reviewing a substantial time period and encompassing outcomes of treatments performed by multiple surgeons is clearly needed.   The aims of the present retrospective study were: 1) to examine the time trends in the incidence of palatal fistula in children with different types of non-syndromic cleft at British Columbia’s Children’s Hospital (BCCH) between 1995 and 2012 2) to identify determinants associated with higher fistula rates. 58      3.2 Materials and Methods The Clinical Ethics Board of the University of British Columbia, Canada (H12-02240) approved the study. The cleft palate database at BCCH was used to access the patients’ medical charts and only charts of non-syndromic patients with a cleft lip and palate deformity were included in the present chart review.   A total of 1050 medical charts patients were available in BCCH’s  cleft palate database from the period of 1995 to 2014. Almost half of these patients (N=456) were either patients with various syndromes or cleft lip patients or patients who had a sub-mucous cleft or a bifid uvula but were categorized under the “unspecified diagnosis” in the database, therefore after being reviewed, were considered non-eligible for the present study. In addition 36 more charts that belonged to patients treated in 2013 or 2014 were not included in the present review since these patients had either not undergone their palate surgery or their post-surgery follow-ups.   After the final selection process, a total of 558 medical charts from the 1995-2012 time period were found eligible for the subsequent retrospective audit. 228 of these patients had unilateral cleft lip and palate (ULCLP), 104 had bilateral cleft lip and palate (BLCLP) and 226 had isolated cleft palate (ICP).  In the present review, the outcome of interest was the presence of the palatal fistula after primary palate surgery. Alveolar 59    fistula and anterior palatal fistula that were intentionally left unrepaired were excluded. The information regarding the presence of palatal fistula was extracted by evaluating the information reported in the medical charts throughout the patient’s entire follow-up period, which for most patients was over 10 years. All data was collected and analyzed by independent researchers.   Patients who were considered eligible for this study were diagnosed with three types of cleft: unilateral cleft lip and palate (ULCLP), bilateral cleft lip and palate (BLCLP) and isolated cleft palate (ICP). Clefts were classified according to the Veau classification, which divides clefts into groups based on the extent of the defect: Veau group I is limited to the soft palate only (ICP); Veau group II involves the soft palate and hard palate (ICP); Veau group III involves the soft and hard palate and lip (ULCLP) and Veau group IV is bilateral complete cleft (BLCLP) (Muzaffar et al., 2001).  The following potential determinants of fistula occurrence were tested: gender, the severity of the cleft (unilateral, bilateral and isolated cleft), type of surgery (Two-flap palatoplasty, Furlow and von Lagenbeck), the time period when the surgeries were performed (earlier surgeries vs. later surgeries) and surgeon’s experience. The operationalization of these determinants can be found in the first column of Table 3-1.   The data was analyzed using IBM SPSS Statistics software (Version 21.0). The bivariate analyses (Chi Square test/Fischer’s exact test) were used to compare fistula rates between 60    gender groups, between surgeons with less and the ones with more experience, among patients with different types of cleft and between earlier years and more recent years. The multivariate logistic regression analysis was employed to identify the determinants associated with higher fistula rates. The threshold for the statistical significance for all tests was set at P< 0.05.   Table 3-1 Risk determinants of fistula occurrence in cleft patients operated at British Columbia’s Children’s Hospital, Canada  (Bivariate Analyses)^  Determinants Fistula occurrence  Significance^   Yes N (%) No N (%)  GENDER Males  92 (30%) 217 (70%)  0.230 Females 59 (27%) 164 (74%) TIME PERIOD Earlier surgeries (1995-2003) 101 (38%) 168 (62%)  <0.001 Later surgeries   (2004-2012) 50 (19%) 213 (81%) SEVERITY OF CLEFT 61     Determinants Fistula occurrence  Significance^   Yes N (%) No N (%)  Unilateral Cleft Lip and Palate 80 (35%) 150 (65%)  <0.001  Bilateral Cleft Lip and Palate 48 (61%)   30 (39%) Isolated Cleft Palate 23 (10%) 201 (90%) SURGERY TYPE  Two-flap palatoplasty 95 (37%) 166 (63%)  <0.001 Furlow 22 (17%) 109 (83%) Von Lagenbeck   2 (5%)   37 (95%) SURGEON’S EXPERIENCE  Less experienced (<100 surgeries) 26 (22%) 90 (78%)  0.046 More experienced(>100 surgeries) 121 (31%) 270 (69%) ^ Chi Square Test or Fisher’s Exact test    62    3.3 Results  Of the 558 patients that participated in this study, 228 had unilateral cleft lip and palate (ULCLP), 104 had bilateral cleft lip and palate (BLCLP) and 226 had isolated cleft palate (ICP). The combined fistula rate in these patients was 28%. The cleft lip and palate patient population was comprised of 59% boys and 41% girls and 28% of the boys and 34% of the girls had palatal fistula after the primary palatoplasty.   The combined fistula incidence rates in cleft lip & palate patients are illustrated in Figure 3-1. Figures 3-2 to 3-4 present the occurrence of fistula during the time period of 1995-2012. These figures present both the percentage distributions and the numerical values for all the years of the retrospective, 1995-2012 evaluation period. The time trends of fistula occurrence in the ULCLP patients are visualized in Figure 3-2. Figure 3-3 shows the trends for the BLCLP patients and Figure 3-4 shows the time trends for the CP patients.   Aim 1: The time trends of palatal fistula in children with different types of cleft.  Prior to presenting findings related to time trends, it is important to emphasize that the total number of cases in each year were relatively small. During the 2003-2012 period, the highest proportions of patients either had unilateral cleft lip and palate (41%) and isolated cleft palate (40%) and the proportion of patients with bilateral cleft lip and palate was 19%. The highest overall fistula rates were associated with bilateral cleft lip and palate (61%) and the lowest with isolated cleft palate (10%). The unilateral cleft lip and 63    palate patients had an overall fistula rate of 35%. Examining the time trends of fistula occurrence across the 1995-2012, evaluation period (Figure 3-1) showed that fistula incidence decreased after 2009 and that no fistulas were reported between 2010-2012.    Figure 3-1 Combined fistula rates in patients with cleft lip and palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital  Fistula occurrence in the ULCLP patients (Figure 3-2) varied substantially among different observation years. No clear time trends can be identified between the years 1995 and 2009 among these patients, i.e. the incidence rates were not consistently ascending or descending. None of the ULCLP patients treated at BCCH Children’s Hospital in the period of 2010-2012 presented with fistula.      0	10	20	30	40	50	60	70	80	90	100	1995	 1996	 1997	 1998	 1999	 2000	 2001	 2002	 2003	 2004	 2005	 2006	 2007	 2008	 2009	 2010	 2011	 2012	64     Figure 3-2 Fistula incidence rates in patients with unilateral cleft lip and palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital  The time trends of fistula occurrence in the BLCLP patients (Figure 3-3) also varied substantially among the different years of observation. The fistula rates in the BLCLP patients (Figure 3-3) were found to be substantially higher when compared to fistula rates in the ULCLP patients (Figure 3-2).  In the BLCLP patients, fistula rates were higher in earlier years compared to later years, however no consistency in the increase or decrease of these rates could be observed.       0	10	20	30	40	50	60	70	80	90	100	1995	 1996	 1997	 1998	 1999	 2000	 2001	 2002	 2003	 2004	 2005	 2006	 2007	 2008	 2009	 2010	 2011	 2012	YES	 NO	65      Figure 3-3 Fistula incidence rates in patients with bilateral cleft lip and palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital   Figure 3-4 demonstrates the time trends of fistula incidence among the ICP patients. One can see that fistula incidence rates in the ICP patients (Figure 3-4) were substantially lower when compared to the incidence rates among patients with the two other types of cleft: unilateral cleft lip and palate (Figure 3-2) and bilateral cleft lip and palate (Figure 3-3).       0	10	20	30	40	50	60	70	80	90	100	1995	 1996	 1997	 1998	 1999	 2000	 2001	 2002	 2003	 2004	 2005	 2006	 2007	 2008	 2009	 2010	 2011	 2012	YES	 NO	66    Figure 3- 4 Fistula incidence rates in patients with isolated cleft palate treated during the 1995-2012 time period at British Columbia’s Children’s Hospital   Aim 2: Determinants of palatal fistula in children with different cleft types.  The potential determinants were associated with fistula occurrence in bivariate and multivariate analyses. The results of bivariate testing are presented in Table 3-1 and the findings of the multivariate testing are shown in Table 3-2. Only significant determinants found in the bivariate testing were included into multivariate logistic analyses.    0	10	20	30	40	50	60	70	80	90	100	1995	 1996	 1997	 1998	 1999	 2000	 2001	 2002	 2003	 2004	 2005	 2006	 2007	 2008	 2009	 2010	 2011	 2012	YES	 NO	67     Table 3-2 Risk determinants of fistula occurrence in cleft patients operated at British Columbia’s Children’s Hospital, Canada  Outcome: Occurrence of fistula#                                                                                                  Model 1. Cohort: Patients with Cleft Palate (all cleft types combined).  Summary: -2 log likelihood=212, P<0.001, Nagelkerke R square=0.199 Determinants tested* Odds ratio 95%CI P value Severity of cleft  3.8 2.0;7.1 <0.001 Time period 1.7 1.1; 2.5 <0.001 Surgeon’s experience 0.3 0.2; 0.4 <0.001 Type of surgery  0.4 0.2; 0.6 <0.001  Model 2. Cohort: Patients with Unilateral Cleft Lip and Palate.  Summary: -2 log likelihood=212, P<0.001, Nagelkerke R square=0.199  Determinants tested* Odds ratio 95%CI P value Time period 4.1 2.1; 8.0 <0.001 Surgeon’s experience 0.4 0.2; 0.7 0.003 Type of surgery  0.7 0.4; 1.2 0.204  Model 3. Cohort: Patients with Bilateral Cleft Lip and Palate Summary: -2 log likelihood=82, P=0.002, Nagelkerke R square= 0.248.                                                                                                     Determinants tested* Odds ratio 95%CI P value 68    Time period 4.2 1.4; 12.3 0.010 Surgeon’s experience 1.4 0.5; 4.1 0.588 Type of surgery  0.6 0.2; 1.8 0.401  Model 4. Cohort: Patients with Isolated Cleft.  Summary: -2 log likelihood=158, P<0.001, Nagelkerke R square= 0.612.  Determinants tested* Odds ratio 95%CI P value Time period 0.6 0.3; 1.3 0.215 Surgeon’s experience 0.2 0.1; 0.4 <0.001 Type of surgery  0.2 0.1; 0.5 <0.001 # Logistic regression. Selection method for determinants: Enter *Determinants tested: Severity of the cleft (bilateral vs. unilateral & isolated cleft), type of surgery (Furlow or von Lagenbeck vs. Two-flap palatoplasty), Time period (earlier surgeries (1995-2003) vs. later surgeries since 2004) and surgeon’s experience (< 100 surgeries vs. >100 surgeries).  The bivariate analyses (Table 3-1) did not find statistically significant gender differences in the palatal fistula occurrence (Chi Square Test, P=0.230). Significantly higher fistula rates (Chi Squared P<0.001) were reported for the BLCLP patients (61%) than for the ULCLP patients (35%) or for the ICP patients (10%). Significant differences in fistula rates were also bivariately associated with the time period in which the surgeries were performed meaning higher fistula rates were reported in earlier years (1995-2003) than in later years (2004-2012). In regards to surgeon’s experience, more fistulas were noted for 69    the surgeons with less experience than the surgeons with more experience. As for surgery type, the highest fistula rate was associated with Two-flap palatoplasty.   The multivariate logistic regression analyses tested the joint effect of the following determinants: the severity of the cleft (BLCLP versus ULCLP and ICP), the time period in which the surgery was performed (1995-2003 vs. 2004-2012) and the surgeon’s experience (<100 surgeries vs. ≥100 surgeries). Table 3-2 presents the results of this multivariate testing which included a total of four models: one where all types of clefts were combined and three additional models, one for each of cleft diagnosis.   Model 1 (fistula rates combined for all cleft types) was highly statistically significant and the determinants/predictors jointly explained about 20% (Nagelkerke R square=0.199) of the variance in the outcome variable (presence or absence of fistula). All determinants tested were statistically significantly associated with fistula occurrence. The strongest determinants of higher fistula rates were the severity of the cleft (OR=3.8, p<0.001) and the time period (OR=1.7, p<0.001) while the strongest determinants of lower fistula rates were: the surgeon’s experience (OR=0.3, p<0.001) and the type of surgery performed (OR=0.4, p<0.001).   The multivariate Model 2 examined determinants associated with fistula occurrence in patients with ULCLP, where both the time period and the surgeon’s experience were found to be significant determinants but the type of surgery was not significantly 70    associated with fistula occurrence. Model 3 presents results related to treating patients with bilateral cleft, where only one significant determinant was found (the time period). The significant determinants in Model 4 were: the surgeon’s experience (OR=0.2, p<0.001) and the type of surgery (OR=0.2).      3.4 Discussion The aims of the present retrospective medical chart review were: 1) to examine the time trends in the incidence of palatal fistula in children with different types of cleft at BCCH, 2) to identify the determinants significantly associated with fistula occurrence.   To the best of our knowledge, the present study is the only independent Canadian study to date that has examined the time trends of fistula occurrence in cleft lip and palate patients and sought to identify the significant fistula-related determinants. Prior to discussing the findings, it is important to emphasize that the total number of cases in each year at  BCCH was relatively small, therefore findings particularly regarding time trends and any comparisons between different years should be interpreted with caution.    No consistent time-related increase or decrease in fistula rates in patients treated at  BCCH during the last 18 years could be identified, although fistula rates at  BCCH were significantly higher in the earlier time period (1995-2003) than in the later years (2004-2012).  The subgroup analyses showed that there were no significant gender associated differences in fistula occurrence, as reported elsewhere (Hardwicke et al., 2014). 71    Concomitantly, our retrospective review showed that higher fistula rates occurred in patients with bilateral cleft lip and palate compared to the two other types of cleft, namely unilateral cleft lip and palate and isolated cleft palate. This finding is not in accordance with the study by Landheer et al. in 2010, which did not find significant differences in fistula occurrence among different Veau classes (Hardwicke et al., 2014).  In the present study, the overall fistula rate in cleft patients was 28%. It is important to consider that a wide range of fistula development up to 78% has been reported in different studies (Bardach et al., 1984; Senders and Sykes, 1995; Mak et al., 2006). The  BCCH data (proportions of different types of clefts and their corresponding fistula rates) was compared to the global data reported in a systematic review by Hardwicke et al. in 2014 (Hardwicke et al., 2014). The proportion of ULCLP of all types of cleft was lower at  BCCH (41%) when compared to the overall global rate (51%), while the proportion of BLCLP in  BCCH (19%) was similar to a global rate (15%)(Hardwicke et al., 2014). The proportion of ICP rates at BCCH (40%) was comparable to a global rate (35%)(Hardwicke et al., 2014). Comparisons of fistula rates between BCCH  and global reports (Hardwicke et al., 2014) showed that fistula rates were substantially higher at  BCCH than reported globally. In order to explain these substantial differences in fistula occurrence between  BCCH and the global rates, it is very important to consider that the present study was performed by independent researchers and included all eligible medical charts and potentially the presence of fistula was measured more accurately in the present study as compared to previous studies. 72     The present study assessed if fistula was recorded throughout a long follow-up period, maximum of 16 years, which should be considered an advantage compared to other studies in which the majority of reports only included short follow-up periods (1 to 3 months), which was possibly too short to allow for multiple examinations necessary to detect all post-operative fistulas. This means that given the long follow-up implemented in the present study, the presence of fistula could be noted and subsequently recorded at different time periods, while other studies seemingly did not have a long follow-up period, consequently their fistula rates might have been potentially underreported. An additional explanation for these substantial differences in fistula rates between the present study and previous studies might be the fact that the global data is mainly accumulated from reports where the lack of independent research can be identified.     Our second aim was to examine potential determinants associated with fistula occurrence. Four potential determinants were evaluated in logistic regression model: the severity of cleft (BLCLP vs. ULCLP or ICP), time period (1995-2003 vs. 2004-2012) and surgeon’s experience (<100 vs. ≥100 surgeries). The significant predictors of higher fistula rates were: the severity of cleft with (OR=3.8) and the time period in which the surgery was performed (OR=1.7), while higher surgeon experience (OR=0.3) and the type of surgery (Furlow/von Lagenbeck vs. Two-flap palatoplasty) (OR=0.4) were significantly associated with lower fistula rates.   73    The limitations of the present study should be acknowledged. It is important to consider that due to the retrospective nature of this study, the source for data collection and analysis was available patients’ charts, which inherently had a substantial amount of missing information. This is in accordance to other retrospective studies that also had the inherent limitation of incomplete records, i.e. missing data which at least limits sub-analyses.   Another limitation of the present study relates to the small number of cases observed in each year. As a result of this fact we could not perform additional sub-analyses that could potentially help us better understand the time trends and their related determinants regarding fistula development in patients with different types of clefts. Thus, future prospective multi-center studies comprising larger samples are needed to provide a clear answer to this research question.   3.5 Conclusions Almost one third of  BCCH patients with cleft lip and palate had a palatal fistula and fistula incidence at this hospital has seemingly declined after 2009.  The highest fistula rates were in patients with bilateral cleft lip and palate and the lowest fistula rates were in patients with isolated cleft palate. The significant risk determinants explaining higher fistula rates were: the severity of the cleft, less experienced surgeons and the time period in which clefts were treated.    74    Chapter 4: A standardized protocol for the prospective follow-up of cleft lip and palate patients 4.1 Introduction Oro facial clefts are common birth defects that may impose a large burden of care on the health, psychological and social wellbeing of affected individuals and their families. The World Health Organization reported the prevalence of cleft lip with or without cleft palate to be 10 in 10,000 births in the United States and worldwide and 12 in 10,000 births in Canada (IPDTOC, 2011).  Cleft palate is a congenital disorder with variable etiology, it can be unilateral or bilateral, complete (with soft palate, hard palate and alveolar ridge involved in the cleft) or incomplete (with soft palate and hard palate involved only up to the incisive foramen) and it can sometimes occur as part of a syndrome (Dong et al., 2012).  The goal of cleft palate repair is to separate the oral cavity from the nasal cavity while allowing for a mobile and functional palate to assist in phonation and deglutition, with minimal adverse effects on maxillary and mid-facial growth (Dong et al., 2012).  Fistula is ‘‘a failure of healing or a breakdown in the primary surgical repair of the palate” (Muzaffar et al., 2001). The occurrence of a postoperative fistula after palate repair remains a considerable challenge in plastic and reconstructive surgery (Parwaz et al. 2009, Losee et al., 2008). The prevalence of cleft palate fistulas ranges from 0 to 78 % (Bardach et al., 1984; Maeda et al., 1987; Senders et al., 1995; Hardwicke et al., 2014) whereas the recurrence rate of repaired palatal fistulas is nearly 100 % (Schultz, 1986; 75    Thaller, 1995). Oronasal fistulas may occur anywhere along the line of the cleft, but the two most common locations are the junction of the hard and soft palate and the anterior portion of the cleft (Muzaffar et al., 2001; Musgrave and Bremner, 1960; O’Neal, 1971). The consequences of oronasal fistulas are: regurgitation of food and fluid into the nasal cavity, and fistulas could also cause escape of air during speech, which results in hypernasality (Inman et al., 2005).   Fistulas are considered clinically significant—functional or symptomatic—when they lead to nasal air escape, speech distortion, hearing loss, or regurgitation of fluid and food into a nasal cavity (Muzaffar et al., 2001; Wilhelmi et al., 2001; Amaratunga, 1988). These problems are complicated by the fact that fistulas are difficult to repair definitively. Several determinants such as age at repair, gender and ethnicity (Landheer et al., 2010), a type of cleft (Veau classification) (Muzaffar et al., 2001; Cohen et al., 1991), width of cleft (Muzaffar et al., 2001; Cohen et al 1991; Helling et al., 2006), longer operation time (Mak et al., 2006) and being operated by surgeons with less experience (Cohen et al., 1991; Emory et al., 1997) have been associated with frequent fistula occurrence.  The nursing care and close supervision with the help of parents may also play a role.   Furthermore, palatal fistulas may be a result of wound breakdown, closure under tension, infection, trauma to the flap, or hematoma (Parwaz et al., 2009). The extent and severity of the cleft have been reported as the two most common predictors of postoperative oronasal fistulas. Patients with a Veau Type III or IV cleft had a significantly higher 76    occurrence of postoperative fistulas when compared with patients classified as Veau Type I or II cleft (Muzaffar et al., 2001; Cohen et al., 1991; Helling et al., 2006). The preoperative cleft width of ≥15 mm and a ratio of cleft width to the sum of the palatal shelves’ width of ≥0.48 have been identified as significant predictors of fistula development (Parwaz et al., 2009).  The 2017 systematic scoping review regarding “Fistula in Cleft Lip and Palate Patients” found only a handful of randomized controlled trials and prospective cohort studies. The field is dominated by weaker study designs such as small studies with less than 30 patients, retrospective cohort studies that inherently have a substantial proportion of missing data and case series which are mainly presentations of a single surgeon’s experience (Salimi et al., 2017). Unsurprisingly, this evidence reported a wide range of primary fistula occurrence and findings, regarding different risk determinants that were not consistent (Salimi et al., 2017). A key reason for this lack of consensus may be the absence of data generated from well controlled, long-term prospective cohort studies comparing several surgical techniques, and outcomes associated with cleft width, cleft type, cleft severity and surgeon’s experience.  There are several challenges in interpreting available evidence, comparing different cleft centers and identifying the most important aspects in cleft patient care. There seems to be no consensus regarding the optimal timing and superior surgical technique for the closure of palatal clefts. The different risk determinants associated with fistula presentation has 77    been a matter of controversy and there is still no definitive evidence regarding any of the previously mentioned risk determinants. In addition, the cleft palate literature surrounding post-operative palatal fistula is difficult to interpret due to ambiguous definitions and a lack of standardization and uniform definition of palatal fistula (Losee et al., 2008). Therefore, the results of different studies cannot be compared with any certainty. (Emory et al., 1997).   A standardized protocol for the follow-up of such patients is needed. Previous attempts such as the Eurocleft study and Americleft study have been conducted to address these problems in a systematic way and to standardize the data collection process as well as monitor cleft patients in a unified manner. This systematic organization of data enabled multicenter comparisons and acquisition of high quality evidence.  The original Eurocleft study started as an intercenter comparison among five cleft centers of the orthodontic records of 9 years old patients with complete unilateral cleft lip and palate. Its main goal was to apply a more strict methodology to intercenter comparisons. It attempted to overcome a part of the limitations and potential biases innate in comparing outcomes reported in the literature from single center studies. In the Eurocleft study craniofacial morphology, nasolabial appearance and dental arch relationships of the same patients were evaluated at the ages of 12 and 17. The last part of the study was directed towards the assessment of parent/patient satisfaction with treatment and to examine associations among patient satisfaction, clinical outcomes and the burden of care. (Shaw, 2005).  78    Americleft following the same study design as the Eurocleft study, was another Intercenter study that examined the treatment outcomes of unilateral cleft lip and palate patients between the ages of 6 and 12 years who were consecutively treated in five well-established cleft centers in North America. The anterior/posterior discrepancy was assessed using lateral cephalograms. Nasiolabial esthetics, documented by patient photographs, was scored using the PAR index and dental arch relationships were evaluated using dental casts and scored according to the Goslon yardstick (Ross, 2011).  However, these inter-center studies had strict inclusion criteria that, in turn limit the external validity for wide applications and patient care.   Except for the Eurocleft study and Americleft study, other inter-center comparisons are uncertain at best due to the heterogeneity of reports, i.e. a variety of non-standardized protocols, variability in the reporting of fistula related outcomes or its determinants, in addition to lack of standardization of the staff who carry out these protocols (Shaw, 2005).  Having a standardized protocol encompassing a comprehensive set of guidelines will enable data collection and comparisons on a global scale.  Consequently, following such a protocol will enable identification of the most important determinants of fistula occurrence. This will lead to acquisition of new clinical evidence for quality patient care as well as advancement of further research.  79    The standardized approach to the follow-up of cleft and lip patients will be useful for multi-center studies as well as for comparisons among individual cleft centers around the world.  In turn, this shared knowledge may, not only produce important evidence but also contribute to better professional care for such patients.  The aims of the present work were: to develop a standardized all-encompassing protocol that takes clinical and research purposes into consideration.    80     4.2 Protocol development and phases 4.2.1 Phase 1: Preparation In preparation for the protocol development, we systematically searched and appraised the available evidence and we also contacted twelve major, North American and international cleft-craniofacial centers.  First, the MEDLINE electronic database was searched using the following combinations of key words: ‘protocols AND cleft palate’, ‘summaries AND cleft palate’, ‘follow-up and cleft palate’ and ‘standardized form AND cleft palate’. This yielded zero results. Using the following keywords’ combination: ‘surveys/questionnaires AND cleft palate’ resulted in 301 papers. Of the total, 146 articles were relevant and of these 50 were focused on quality of life, 12 researched treatment-related outcomes, 34 were risk determinant studies, 3 examined the burden of patient care, 43 inquired about parents/patients perceptions on cleft care and the sociological and psychological impact of cleft, 3 studies evaluated feeding methods for cleft babies. In addition, one survey of multidisciplinary cleft team examination format was found, in which frequency of team meetings, funding and parent/patient satisfaction-related information could be found.  To be as comprehensive as possible in determining the availability of any such protocol, major cleft centers around the world were contacted and we inquired about their cleft lip and palate patient management process.  A total of 13 cleft-craniofacial centers, 2 81    Canadian, 10 North American and 1 Brazilian cleft center were contacted by email and/or phone and seven responded. The interviews with representatives from these centers revealed that the majority of them do not have a standardized comprehensive strategy for reporting and follow-up of cleft lip and palate patients. Consequently, documentation regarding the type and size of cleft, presence or absence of fistula along with other important information is at the discretion of the cleft team and what they consider necessary to note in the team reports or operative reports.   The most comprehensive assessment form belonged to the cleft-craniofacial center at the Children’s Hospital of Pittsburgh. This team utilizes the L-A-H-S-H-A-L method (Kriens, 1989) for cleft classification, reports the width of the cleft, the size of fistula in millimeters and its location using the Pittsburgh fistula classification system (Smith et al., 2007). All data is then entered into electronic medical records.   The cleft-craniofacial team at the Sick Kids Hospital in Toronto has a very thorough reporting system for the original cleft defect. The cleft status, location and severity are documented. Information regarding the lip, alveolus, arch form, primary hard palate, vomer, secondary palate and VPI (velopharyngeal insufficiency) are recorded according to the L-A-H-S-H-A-L method (Kriens, 1989). Demographic data and information about the plastic surgeon performing the procedure is also noted. Information regarding the postoperative fistula is dictated by the plastic surgeon, which then also draws a picture to 82    describe the location of the fistula. All collected information is then entered in the database.  4.2.2 Phase 2: Identifying potential risk determinants  In preparation for the development of a standardized all-encompassing protocol for the systematic reporting of all potential risk determinants of fistula development, the available evidence was reviewed. Potential risk determinants from four different domains were identified.   1) Demographic Domain (age, gender, ethnicity, family history)  Age at time of repair, gender and ethnicity have been associated with fistula occurrence (Landheer., 2010). On the other hand, several other studies which examined age and gender as potential predictors of fistula occurrence in cleft lip and palate patients, did not find age and gender related differences in fistula occurrence (Emory et al., 1997, Parwaz et al., 2009). Nonetheless, demographic information is important, therefore the standardized protocol needs to include this information.   2) Cleft Domain (type of cleft, width and length of the cleft, ratio of the width of the cleft to the sum of the width of the palatal shelves) Formation of postoperative fistula has been associated with the width of the cleft, deficiency of the palate segments, misplacement and distortion of the cleft segment (Boyne, 1970). An increased probability of fistula formation has also been related to 83    increased defect size as in bilateral cleft palate and complete cleft palate defects (Cole et al., 2006).  The study by Shultz 1989 found that fistula formation was related to the relative width of the palate as measured between the tuberosities and the width of the cleft as measured between the tuberosities (Elbel, 1985). When this ratio was higher than 30 the probability for fistula formation became 8 times stronger (Shultz, 1989).   A study by Parwaz et al. also emphasized the importance of the ratio of cleft width to the sum of the palatal shelves (Parwaz et al., 2009). Most experts agree that the extent and magnitude of the preexisting cleft are the strongest factors for predicting the development of postoperative oronasal fistulas. Patients with a Veau Type III or IV have a significantly higher incidence of postoperative fistulas compared with patients classified as Veau Type I or II (Muzaffar et al., 2001; Cohen et al., 1991; Helling et al., 2006).   It was found that the width of the cleft palate has a bearing on the occurrence of postoperative palatal fistula formation. Width of 10 mm or more was identified as a risk for fistula formation (Wilhelmi et al., 2001; Helling et al. 2006; Bresnick et al., 2003; Parwaz et al., 2009).  84    3) Surgery Domain (surgeon’s experience, type of palate surgery, timing of surgery, length of surgery, surgical complications and post surgical management) Surgeon’s experience and the selection of surgical procedures have also been associated with fistula presentation (Muzaffar et al., 2001; Cohen et al., 1991; Bekerecioglu et al., 2005; Bindingnavele et al., 2008; Mak et al., 2006). Experienced surgeons had better outcomes than less experienced ones (Mulliken, 2004; Shaw et al., 1992). Other potential fistula-related risk determinants were the timing of the repair and accuracy in the surgical performance (Parwaz et al., 2009; Murthy et al., 2009, Salyer et al., 2006). It has been reported that early dehiscence and fistulas are primarily caused by errors in technique such as inadequate mobilization, closure under tension, injury at re-intubation, poor handling of tissues, failure to achieve a layered closure, post- operative bleeding or infection (Campbell, 1962).  In addition, consumption of hard food soon after surgery and manipulation of the surgical site by the patient were related to early wound failure (Kent and Martin, 2009). 4) Palatal Fistula Domain (presence/absence of a primary/secondary/tertiary fistula, fistula width, length, location, symptomatic/asymptomatic manifestation, type of surgery, surgeon’s experience) Although oronasal fistulas may occur anywhere along the line of the cleft, two most common locations are at the junction of the hard and soft palate and at the anterior portion of the cleft (Muzaffar et al., 2001; Musgrave and Brenner, 1960; O’Neal, 1971).  85    4.2.3 Phase 3: Standardized protocol for the prospective follow-up of cleft lip and palate patients  This protocol was designed with the purpose of collecting information about multiple potential determinants of palatal fistula. In order to fulfill this objective we have designed a comprehensive assessment form that inquiries about and reports on multiple aspects of patient intake and management. This protocol standardizes how information about the potential risk determinants will be reported, which in turn may lead to quality assurance in patient management and can also facilitate future comparative studies across centers.   The protocol consists of the following domains of determinants: 1) the socio-demographic domain (age gender, ethnicity and genetic background), 2) the cleft defect domain (the width, length, type or severity of the cleft), 3) the surgery domain (timing of surgery, type of surgery, surgeon’s experience, complications during and after surgery) and 4) the fistula domain (presence/absence of a primary/secondary/tertiary fistula, its width, length and location and symptoms). The complete standardized form with its components is presented in Appendix A.  4.3 Discussion The present work aimed to develop a standardized comprehensive all-encompassing protocol enhancing the systematic follow-up of cleft patients.  Such protocol is important for quality assurance in the care of these patients.  Our systematic scoping review on palatal fistula in cleft lip and palate patients Salimi 2017 and our retrospective follow-up 86    study performed in one of the major cleft craniofacial centers Salimi 2016 have demonstrated that high quality studies in this field are mainly lacking. Therefore, the application of this standardized protocol will enable improvement of patient care as well as provide a useful tool to enable future prospective cohort studies to be conducted in a systematic manner and according to specific guidelines.  We recognize that the protocol is rather comprehensive as it includes multiple items from all four domains.  If necessary, different cleft centers can select separate parts of this protocol depending on their resources, specific needs and requirements. Implications of the present work is that it can be used for both clinical and research purposes. Most importantly, the use of such protocol can facilitate the quality assurance in the medical care of cleft patients.  The standardized protocol will also ensure comparisons and sharing of experiences among multiple centers on the basis that these cleft centers will be collecting data according to a unified standardized protocol. Given limited human resources in most cleft centers, information can also be collected using voice activation technology.  We acknowledge the inherent challenges of the comprehensive documentation of information for such patients, for example, measuring the size and width of the cleft.  Given that taking impressions of a cleft baby cannot be ethically justified since it does not benefit the patient, our suggestion would be to take an occlusal photograph of the palate before the surgery at a specified time point for example, when the baby is 7 days 87    old.  In order to standardize subsequent comparisons, such photographs can be scaled, by having a small ruler taped onto the occlusal mirror. The ratio of the width of the cleft to the width of the palatal shelves can be the gauged by measuring the maxillary inter tuberosity distance at the same time as when the occlusal image is taken. This will provide us with the size of the cleft and the ratio of the cleft to the sum of the palatal shelves. Currently available intra oral cameras are too large to be operated in a newborn’s mouth. In addition, intra oral scans of edentulous surfaces are not accurate. We can expect that new technology will help facilitate the scanning process in the near future.   4.4 Conclusion Implementing a standardized prospective follow up protocol will prevent the aforementioned deficiencies, in the current medical reporting. The proposed protocol has a potential to enhance the quality of patient care by ensuring that multiple patient related aspects are consistently reported. It may also facilitate future multicenter research, which is needed to reduce fistula occurrence in cleft lip and palate patients.     88    Chapter 5:  Post-operative Palatal Fistula, Our Knowledge and Our Needs. The goal of our first project was to conduct a systematic scoping review of the literature surrounding palatal fistula in order to gather information about the level and quality of the evidence in this field. Performing systematic reviews has been the common approach for synthesizing primary evidence. Scoping reviews on the other hand have only gained popularity in more recent years (Daudt et al., 2013). The commonalities of systematic reviews and scoping reviews are that they both thoroughly search the literature, in an attempt to identify all available sources of evidence. However, there are some major differences between these two types of reviews. First, systematic reviews most commonly focus on a specific research question. Second, systematic reviews apply standardized inclusion/exclusion criteria and preselect studies based on their quality for the subsequent knowledge synthesis. Scoping reviews, on the other hand, commonly address several research questions at a time and have less limiting inclusion/exclusion criteria for the selected studies (Arksey and O’Malley, 2005). Therefore, the main objective of systematic reviews is to obtain a valid answer to a specific research question while scoping reviews aim to present a broader picture of all available evidence (Armstrong et al, 2011; Colquhoun et al., 2014).   Another key difference between the two is that systematic reviews provide knowledge synthesis using a reduced number of high quality studies, whereas scoping reviews 89    synthetize information from a wider range of studies and the quality of these studies is not assessed (Arksey and O’Malley, 2005).  It is important to consider that both systematic and scoping reviews have their pros and cons. The main advantage of systematic reviews is that they gather the highest level of evidence to answer a specific research question since the preselected studies used for the research synthesis are of high quality, but on the downside systematic reviews frequently conclude that the available evidence is inconclusive (Smaïl-Faugeron et al., 2014). This inconclusive evidence commonly resulting from systematic reviews, clearly, creates a dilemma for clinicians who need to make their everyday decisions based on the best available evidence, which according to the systematic reviews, are non-existent. On the other hand, scoping reviews, which need less preparation because they preselect studies, can be a useful alternative strategy for the systematic overview of available evidence. They can also be useful for assisting clinicians in their day-to-day treatment-related decisions. A scoping review is a useful strategy for knowledge synthesis that incorporates different study designs and comprehensively synthesizes information from primary sources of evidence with the goal of updating the knowledge of practitioners, program directors, and policy makers. It also has the potential to guide future research (Arksey and O’Malley, 2005; Colquhoun et al., 2014).   The main limitation of scoping reviews is that they do not assess the quality of the primary sources of evidence. However, this limitation can be addressed by incorporating 90    some guiding principles designed for systematic reviews into the scoping review protocols. Therefore, we decided to perform a systematic scoping review, which combines the principles from both systematic and scoping reviews to guide our broad overview of the evidence regarding fistula occurrence that was published in multiple databases.  In order to assess primary sources of evidence, we extracted reports from multiple original studies. In our systematic scoping review, we identified two main research areas, surgical repair of the cleft deformity and the potential risk determinants of fistula occurrence in cleft lip and palate patients.   The Hierarchy of Evidence places high quality randomized controlled trials at the top of the evidence pyramid as best primary evidence pertaining to treatments namely surgeries, whereas the study of prognostic and risk factors is best addressed with prospective cohort studies (Parfrey and Ravani, 2015).  Of note is that the present systematic scoping review only found a few randomized trials and a few prospective cohort studies, whereas the majority of the research in this field is dominated by weaker study designs, such as small studies with sample sizes of less than 30 patients, retrospective cohort studies that commonly have a substantial proportion of missing data and case series which usually are presentations of a single surgeon's experience.   91    Our knowledge synthesis of this relatively low-quality primary evidence identified a wide range of primary fistula occurrence in both types of studies. No significant difference was found in the fistula rates between the older studies compared to more recent studies and no significant differences in fistula rates were noted among different quality studies. Multiple risk determinants were studied and age at surgery, surgeon's experience, type and severity of the cleft were the most frequently examined risk determinants. It is important to consider that findings pertaining to different risk determinants and fistula occurrence have been inconsistent (Salimi et al., 2017).  By evaluating the quality of evidence we found that the research mainly focused on surgeries and fistula-related risk determinants. The available evidence was of low level and poor quality. We could not determine a consistent pattern between fistula occurrence and any of the risk determinants. When comparing older studies to more recent ones, fistula rates did not differ significantly. Finally, the quality of the studies was not associated with a difference in the fistula rates (Salimi et al., 2017).   Limitations of the present systematic scoping review are as follows: first, both types of original studies were heterogeneous. Therefore, we could not perform subgroup analyses that could have potentially produced additional important knowledge, particularly about risk determinants of fistula occurrence in cleft lip and palate patients. Second, we needed to adjust both CONSORT and STROBE checklists for the quality evaluations of available studies. Due to this adjustment, the quality of the studies in the field that we reviewed 92    could not be directly compared with the quality of reports in other medical fields (Salimi et al., 2017).  Having thoroughly reviewed the scientific evidence we came to the conclusion that there is no standardized approach to reporting fistula rates. In addition, there is little high quality evidence and the field is mostly dominated by small studies such as case reports, case series and retrospective reviews. Moreover, only a few Canadian studies have been done on this subject and the focus for the most part has been on the aboriginal population. We deemed it necessary to know the fistula rates of patients treated for cleft palate deformity in British Columbia’s major cleft center. We were also interested in knowing how the incidence of fistula at BCCH compares to the rest of the world.  Therefore, we conducted an 18 years retrospective chart audit by examining the medical records of cleft lip and palate patients treated at BCCH’s cleft center (Salimi et al, 2016). A total of 1050 patients’ medical charts were available in BCCH’s cleft palate database from the period of 1995 to 2014. After applying the inclusion/exclusion criteria, a total of 558 medical charts from the time period of 1995–2012 were found eligible for the subsequent retrospective audit (Salimi et al, 2016).  Patients who were considered eligible for this study were diagnosed with three different types of cleft: unilateral cleft lip and palate (ULCLP), bilateral cleft lip and palate (BLCLP), and isolated cleft palate (ICP). Clefts were classified according to the Veau 93    classification, which divides clefts into groups based on the extent of the defect: Veau group I is limited to the soft palate only (ICP), Veau group II involves the soft palate and hard palate (ICP), Veau group III involves the soft and hard palate and lip (ULCLP), and Veau group IV is bilateral complete cleft (BLCLP) (Muzaffar et al., 2001). Of the total 558 patients, 228 had unilateral cleft lip and palate (ULCLP), 104 had bilateral cleft lip and palate (BLCLP), and 226 had isolated cleft palate (ICP) (Salimi et al, 2016).  In this study, the outcome of interest was the presence of a palatal fistula after primary palate surgery. The information regarding the presence of palatal fistula was obtained by evaluating various reports such as team reports and operative reports in the patient’s medical charts throughout the entire follow-up period. In this study, the follow-up period for the majority of patients was over 10 years. A team report is a collective review and treatment plan for each patient gathered by the cleft palate team, which consists of a nurse team coordinator, plastic surgeon, an orthodontist, a pediatrician, an audiologist, an otolaryngologist and a speech pathologist. An operative report is a written description of the operative procedure. All data were collected and analyzed by independent researchers. To increase the validity of the data, we only included the information from surgeons who had completed 10 or more surgeries at BC Children’s Hospital (Salimi et al, 2016).  The following potential determinants of fistula occurrence were examined: gender, severity of the cleft (unilateral, bilateral, and isolated cleft palate), type of surgery (Two-94    flap palatoplasty, Furlow palatoplasty, and von Lagenbeck palatoplasty), the time period in which the surgeries were performed (before the year 2006 vs. after the year 2006), and surgeon’s experience (Salimi et al, 2016).  Our retrospective review concluded that nearly one out of four patients with cleft who were treated at BCCH presented with a post-operative palatal fistula. The study also found that the incidence of fistula declined after 2009. The highest fistula rates were in patients with BLCLP, and the lowest fistula rates were seen in patients with ICP. The significant risk determinants in regards to higher fistula rates were severity of the cleft, less experienced surgeons, and the time period in which clefts were treated. Although it is important to note that the documentation of individual operator skills remains elusive and therefore, a source of proficiency bias (uncertainty about level of surgical expertise) that is uncontrolled in a retrospective audit (Salimi et al, 2016). Retrospective research involves the analysis of data that were not originally collected for the purpose of research. This retrospective data includes physician and nursing notes, ambulatory and emergency room reports, consultations, admission and discharge documentation, laboratory and diagnostic testing reports, and other clinical or administrative data (Gearing et al., 2006). For over eighty years, the systematic review of historical records has guided various, clinical research. The scientific evaluation of existing health records is a usual practice in epidemiological investigations, quality assessment studies, professional education, 95    residency training and clinical research. Research using retrospective chart reviews has been reported to comprise 25% of all scientific articles in emergency medical journals (Gearing et al., 2006). Some of the advantages of conducting retrospective chart reviews include: a practical and relatively inexpensive research method to explore rich and easily accessible existing data sources; better access to examine medical conditions where there is a long latency between exposure and disease, which in turn allows for the study of rare diseases and most importantly, the generation of hypotheses that can then be tested prospectively in future research (Gearing et al., 2006). However, there are some significant limitations in regards to retrospective studies such as incomplete documentation, missing charts, unrecoverable or unrecorded information, difficulty interpreting information found in the documents (e.g. jargon, acronyms, photocopies), problematic verification of information, difficulty establishing cause and effect and inconsistency in the quality of information recorded by medical professionals, which have discouraged researchers from widely adopting this methodology (Gearing et al., 2006). It is true as mentioned above that with every retrospective audit of available data there are challenges in regards to incomplete records and vague definitions and our research project was no exception. Surgeons were found to be lacking in regards to consistently reporting outcomes, specifically their complications. From our experience we realized 96    that in the medical charts, fistulas were mentioned but often not sufficiently described, meaning that location, size and type of fistula were not recorded. In many instances the fistula was noted by the speech pathologist rather than by the treating surgeon.   Additionally, ‘‘a fistula was noted’’ would be all that could be found in a medical chart. Such common deficiencies have been reported elsewhere as well (Losee et al., 2008). To compare our rates with the global data reported we utilized a systematic review conducted by Hardwicke et al. in 2014. We found that the proportion of ULCLP of all types of cleft was lower at BCCH (41%) compared with the overall global rates (51%), while the proportion of BLCLP at BCCH (19%) was similar to the global rates (15%) (Hardwicke et al., 2014). The proportion of ICP rates at BCCH (40%) was comparable to the global rates (35%) (Hardwicke et al., 2014).  When we compared fistula rates between BCCH and global reports (Hardwicke et al., 2014) we noticed that BCCH fistula rates were substantially higher than reported globally. However, a few crucial points need to be considered. The present study was performed by independent researchers, it included all relevant medical charts, and employed a long-term follow-up (Salimi et al., 2016), while the Hardwick review synthesized data from primary sources of evidence, which seemingly were not originating from independent research, nor did they include long-term follow-ups.   97    Consequently, we believe that there is potential for the underreporting of fistula rates in the global literature. Our belief is supported by our systematic scoping review, in which we identified a potential for information bias due to the following facts: only ¼ of surgery-related studies reporting fistula rates had independent examiners, only ½ of such primary studies included all consecutive patients in their sample for the data analysis, and only 66% of these studies had a follow-up of three months or more (Salimi et al., 2016).   Another noteworthy fact about the present BCCH study was that we assessed the presentation of fistula throughout a long follow-up period (maximum of 16 years), which is an advantage compared to other studies in which the majority only included short follow-up periods of 1 to 3 months. The relatively brief follow-up period in the previous studies was possibly insufficient to detect all postoperative fistulas. This could mean that given our long follow-up, the presence of all fistulas could be detected and subsequently recorded at different time periods, whereas in the majority of previous studies without a long follow-up period, fistulas might have gone undetected.  An additional explanation for these substantial differences in fistula rates between our retrospective chart audit and previous studies could be the fact that the global data are collected mostly from studies in which the lack of independent research can be identified whereas one of the strengths of our retrospective chart review was that the primary investigator had no connections to the BCCH’s cleft and craniofacial team, therefore reducing the potential for information bias. 98    We have identified a gap in present cleft research and that is the lack of a standardized data collection protocol pertaining to cleft, in general and fistula in particular. There is also no consensus regarding the anatomical description of reported fistulas, which results in a significant lack of internal and external validity. This in turn, makes inter-center, surgeon-specific, and procedure-related comparisons less feasible. Therefore, an anatomically based numerical classification system is a necessary part of a complete cleft palate assessment form. As a result of proper documentation, the data will be recorded more accurately and it will help prospectively remove any vagueness as currently observed in the literature, which will in turn facilitate future comparative studies across different cleft centers.   The fundamental limitation of inter-center comparisons is that, they cannot differentiate between the impact of the different individual elements of a center’s protocols on its outcomes, nor can they differentiate between its protocols, or the influence of the staff members who follow those protocols (Shaw et al., 2005; Eurocleft Study-Part 5). Although if a series of multicenter comparisons with a large number of cases were to be conducted, then eventually one of these centers would rise up as the most successful one for a certain outcome, but even then this would have limited value for the clinical community since only protocols can be transferred and not clinicians. Certainly, defining whether a protocol or its elements are good or bad needs the well-defined criteria of a randomized clinical trial (Shaw et al., 2005; Eurocleft Study-Part 5). 99    The most common type of presenting outcomes has always been individual reports at centers. The reason for performing these reviews is not always clear. They could be done to allow teams to evaluate the success of their chosen protocol in comparison to the published reports. On the other hand, these reports may be prepared when the authors believe that they have created a superior protocol, and the data is presented to validate their choice and urge others to follow their lead (Shaw et al., 2005; Eurocleft Study-Part 5).  But for the team preparing the report and for others who are interested in interpreting the results, there are fundamental problems in making comparisons with other reports due to the undeniable presence of a set of potential biases (WHO, 2002), namely: proficiency bias, susceptibility bias, follow-up bias, exclusion bias, analysis bias and reporting bias (Shaw et al., 2005; Eurocleft Study-Part 5).  Single center and multicenter comparisons are predisposed to the aforementioned biases. However, the greater transparency of multicenter comparisons should increase their reliability, consequently their external validity. For example, rules that are agreed upon by collaborators at the beginning and external checks of records should decrease selective loss to follow-up and late exclusion of less successful cases. The strongest advantage of multicenter comparisons is the standardization of analysis and minimization of reporting bias. Single center studies are usually conducted behind closed doors but in a multicenter study the analysis and reporting part is usually a corporate activity and therefore, 100    procures greater objectivity. The statistical comparison is also simplified across a joint data set, whereas there is rarely sufficient information available to allow statistical comparison between single center reports (Shaw et al., 2005; Eurocleft Study-Part 5). Perhaps the greatest advantage of multicenter studies is the cooperative spirit they promote, and the gradual decrease of rivalry that takes place. Close working also allows the sharing of past successes and failures and specifically enables productive joint working with a potential to acquire high quality clinical evidence (Shaw et al., 2005; Eurocleft Study-Part 5).  This being said, despite the many advantages discussed above, there are two important limitations to the use of multicenter studies as the routine method of clinical research. First, multiple inter-group comparisons increase the total sample of cases required to have a higher power for conducting comparisons. Secondly, the logistic challenges and the expense of meetings may be extensive (Shaw et al., 2005; Eurocleft Study-Part 5). A standardized protocol encompassing a comprehensive set of guidelines will enable data collection and comparisons on a global scale. This protocol will help identify the most important determinants of fistula occurrence which will in turn lead to the attainment of new clinical evidence for quality patient care as well as advancement of further research. The standardized approach to the follow-up of cleft and lip patients will be useful for multi-center studies as well as for comparisons among individual cleft centers around the world. Consequently, this shared knowledge may not only produce important evidence but may also contribute to better professional care for cleft palate patients. 101    Although we acknowledge the potential challenges of the comprehensive documentation of information, we believe that the benefits of the extensive and standardized data collection far outweigh the challenges. The protocol we developed is unique in the sense that it is the first of its kind. Furthermore, it is the only solution in our opinion to prospectively preventing deficiencies in medical reporting. The proposed protocol has the potential to increase the quality of patient care by ensuring that multiple patient-related aspects are not only consistently reported but also analyzed. It may also enable future multicenter research, which as mentioned before, is necessary to reduce fistula occurrence in cleft lip and palate patients.    Future Research: Patient/Parent Satisfaction Assessing the satisfaction of patients and caregivers with the treatment they have received from the cleft team and exploring the interrelationships between, patient satisfaction, objectively rated outcomes, and the burden of care is an aspect of care that needs to be explored in the future (Semb et al., 2005; Eurocleft study-Part 4).  Satisfaction can include the patients’ and parents’ interpretation of the manner in which they were cared for, the results that were achieved and the possible shortcomings in services that can be improved going forward (Semb et al., 2005; Eurocleft study-Part 4). Adequacy of treatment can be gauged by asking parents and patients whether the amount of information satisfied their needs. Parents and patients can be asked about what would be the best way to provide information to them. Options can be having a private chat with 102    the specialist who is providing the new phase of treatment, a meeting where the whole team of specialists are present, passed on as written information or any other mode of communication that the patient or parent requests. Responsiveness of the specialist to the patients’ and his/her parents’ questions and concerns can also be evaluated. Satisfaction with treatment can be investigated by asking questions regarding the patients’ and parents’ level of satisfaction with the appearance of the lip, nose, teeth and speech. Teasing incidents and the subject of teasing whether it is the nose, lips, teeth or speech should also be documented. 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J Craniofac Surg 2011 Nov;22(6):2006-10.   132     Appendix A: Standardized Cleft Lip and Palate Patient Assessment Form  Patient Name:  Date:  Diagnosis:  Date of Birth:  Gender:  M   F  Other  Home Address: City:  Province:  Country:  Patient’s Ethnicity: Caucasian African American Asian Aboriginal Hispanic Other (specify):     133    1 Type of cleft based on Veau classification:   A)Veau Class I: Soft palate only  B)Veau Class II: Hard and soft palate to the incisive foramen  C)Veau Class III: Complete unilateral of soft, hard, lip & alveolar ridge  D)Veau Class IV: Complete bilateral of soft, hard and/or lip & alveolar ridge                                                             Figure 1:  The Veau Classification of Palatal Clefts               “Cohen et al., 1991”                                                                                           2 Width of cleft (transverse dimensions): ………mm 3 Length of cleft (anterior/posterior dimensions): ……….mm 4 Width of palatal shelves: Right ……mm / Left …..mm 5 Type of lip surgery (specify): 6 Age at lip surgery (specify): 7 Surgeon performing lip surgery: 134    8 Approximate number of lip surgeries performed by this surgeon: 9 Type of palate surgery (specify): 10 Age at palate surgery (specify in months): 11 Surgeon performing palate surgery: 12 Approximate number of palate surgeries performed by this surgeon: 13 Length of palate surgery: ……. minutes 14 Weight at the time of surgery: ……. lbs 15 Tissue friability  Yes  No 16 Blood loss during surgery: ……. cc 17 Post surgical management:  Bottle                       # of days  Nipple                      # of days  Pacifier                    # of days  Elbow restraints   # of days Food restrictions or special diet  Yes No   Specify:……………………….. 18 Primary Fistula:  Yes  No Date of assessment: ……………………. 19 Primary Fistula:  None Symptomatic   Non symptomatic 20 Fistula symptoms: Nasal regurgitation  Speech disorder Other 21 Width of primary fistula (transverse dimensions): ……….mm 22 Length of primary fistula (anterior/posterior dimensions): ………mm 23 Date of primary fistula detection:   mm/dd/yyyy……………………… 135    24 Primary fistula classification: Type I: Uvular  Type II: Soft palate  Type III: Junction of hard/soft palate  Type IV: Hard palate                                           Type V: Junction primary/secondary palate  Type VI: Lingual alveolar  Type VII: Labial alveolar  Figure 2: “Pittsburgh fistula classification system”  Smith et al. 2007 25 Secondary fistula:  Yes  No  Date of assessment ………… 26 Secondary fistula:  None Symptomatic   Non symptomatic 27 Fistula symptoms: Nasal regurgitation  Speech disorder Other 136    28 Width of secondary fistula (transverse dimensions): ……….mm 29  Length of secondary fistula (anterior/posterior dimensions): …..mm 30 Date of secondary fistula detection:   mm/dd/yyyy 31 Secondary fistula classification: Type I: Uvular  Type II: Soft palate  Type III: Junction of hard/soft palate  Type IV: Hard palate                                           Type V: Junction primary/secondary palate  Type VI: Lingual alveolar  Type VII: Labial alveolar  Figure 2: “Pittsburgh fistula classification system”  Smith et al. 2007 137    32 Type of palate surgery for secondary fistula repair (specify):…… 33 Age at palate surgery for secondary fistula repair (in months):……. 34 Surgeon performing palate surgery for secondary fistula repair: 35 Approximate number of palate surgeries for fistula (primary/secondary/tertiary) repair performed by this surgeon: 36 Length of palate surgery for secondary fistula repair: ……… minutes 37 Weight at the time of secondary fistula repair surgery: ………. lbs 38 Blood loss during secondary fistula repair surgery: …………. cc 39 Post-surgical management:  Bottle                       # of days  Nipple                      # of days  Pacifier                     # of days  Elbow restraints          # of days Food restrictions or special diet  Yes No   Specify:……………………….. 40 Tertiary fistula:  Yes  No  Date assessed: ……………………… 41 Tertiary fistula: None Symptomatic   Non symptomatic 42 Fistula symptoms: Nasal regurgitation  Speech disorder Other 43 Width of tertiary fistula (transverse dimensions): ……..mm 44 Length of tertiary fistula (anterior/posterior dimensions): ……mm 45 Tertiary fistula classification:   Type I: Uvular  138    Type II: Soft palate  Type III: Junction of hard/soft palate  Type IV: Hard palate                                           Type V: Junction primary/secondary palate  Type VI: Lingual alveolar  Type VII: Labial alveolar   Figure 2: “Pittsburgh fistula classification system”  Smith et al. 2007 46 Type of palate surgery for tertiary fistula repair: 47 Age at palate surgery for tertiary fistula repair: 48 Surgeon performing palate surgery for tertiary fistula repair: 49 Approximate number of palate surgeries for fistula repair (primary/secondary/tertiary) 139    performed by this surgeon: 50 Length of palate surgery for tertiary fistula repair: …… minutes 51 Weight at the time of tertiary fistula repair surgery: ……. lbs 52 Blood loss during tertiary fistula repair surgery: ……. cc 53 Post surgical management:   Bottle                      # of days  Nipple                     # of days  Pacifier                    # of days  Elbow restraints      # of days Food restrictions or special diet  Yes No   Specify:………………………..             140    Appendix B: Cleft Patient Caregiver Orientation Section Palatal fistula is a common side effect of cleft palate surgery. It is defined as an unintentional communication between the mouth and the nose that occurs after the surgical correction of the cleft. Our comprehensive review of the literature showed that the quality and level of evidence surrounding fistula is poor.  In order to determine the fistula rates and the significant factors that play a role in the development of post surgical fistula, an 18 years chart audit of the medical records of cleft patients at British Columbia’s Children’s Hospital was conducted and factors such as severity of the cleft and experience of the surgeon were identified to be instrumental in fistula development.  As a result of this research the need for an all-encompassing protocol was determined and subsequently developed to help identify and record as many patient related factors as possible to aid patient care and to facilitate future research.  

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