Systematic Literature Review
The electronic search returned 514 articles; an additional 68 were identified from a manual search of other sources; 121 duplicates were deleted. Of the 461 records screened based on their titles and abstracts, 316 were included in the full-text assessment. Of those, 149 were excluded based on the inclusion/exclusion criteria (Fig. 1). A total of 16 studies were included in the qualitative synthesis for RVF and AVF: 14 addressing RVF only, 1 addressing AVF only, and 1 addressing both RVF and AVF (combined) (Table 1).
Table 1
Characteristics of papers included in the SLR (n = 16 studies)
Author, year | Country, location | Inclusion criteria | Exclusion criteria | Fistula type | Sample size | Intervention(s) | Risk of bias (ROBINS-I) |
Corte, 2015 [9] | France, Beaujon Hospital, Paris | Women undergoing surgery for RVF (1996–2014), includes multiple etiologies (CD, post-operative, obstetrical, post-radiation, pelvic cancer, diverticulitis, trauma, unknown) | Not reported | RVF | 79 RVFs | Conservative procedures: seton drainage, vaginal advancement flap, rectal advancement flap, diverting stoma only, fistula plug, fibrin glue Major procedures: GMT, biomesh interposition, standard CAA or CRA, delayed CAA, abdominoperineal excision | Moderate |
El-Gazzaz, 2010 [14] | USAa | Women with CD-related RVF who underwent surgical repair with intent to close the fistula from 1997 to 2007 | Surgical procedures not intended for fistula closure (e.g., seton placement, diverting stoma alone, or definitive proctectomy without reconstruction) | RVF | 65 RVFs | Advancement flap, CAA, episioproctotomy, fibrin glue, plug | Moderate (ClinRO) Serious (PRO) |
Gaertner, 2011 [15] | USAb | Women with CD who underwent operative treatment for RVF between March 1998 and December 2005 | Perianal fistula | RVF | 51 RVFs | Operative treatment, operative treatment + infliximab | Moderate |
Göttgens, 2017 [27] | Netherlands, IBDSL registry | Women with CD diagnosed January 1991–July 2011 at age ≥ 18 years | Not reported | RVF | 17 RVFs | N/A | Low |
Haennig, 2015 [10] | France, gastroenterology department, Hôpital Rangueil, Toulouse | Women with a perianal CD anorectal or vaginal fistula referred between 2000 and 2010 | Patients with follow-up < 6 months or with enteric fistula or ECF | RVF | 12 RVF | Seton drainage and associated treatment, infliximab, external drainage, fibrin glue, advancement flap, fistulotomy Other treatments (external drainage + infliximab, fistulotomy + infliximab, advancement flap + infliximab, infliximab [monotherapy], external drainage, bowel diversion) | Moderate |
Jarrar, 2011 [16] | USA, Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, OH | Women who underwent transanal endorectal advancement flap repair of complexc anal fistula by the same surgeon from 1995 to 2005 | Patients with subcutaneous and superficial trans-sphincteric fistulas treated with fistulotomy alone or fistulotomy and a cutting seton | AVF | 21 AVFs | Transanal endorectal advancement flap repair | Moderate |
Korsun, 2019 [17] | Germany, surgery departments of the University Hospital Regensburg and the St Josef Hospital Regensburg | Women with AVF, RVF, rectourethral fistulas, or pouch-vaginal fistulas and diagnosed with IBD who underwent GMT or re-transposition for a recurrent fistula between January 2000 and May 2018 | Patients with IBD who underwent GMT strictly owing to fecal incontinence and not for fistula treatment | RVF | 21 RVFs 2 AVFs | GMT | Moderate |
Manne, 2016 [26] | USA, Department of Medicine—Gastroenterology, University of Alabama at Birmingham, Alabama | Women with CD who underwent RVF surgery (either mucosal flap surgery or seton placement) between 2000 and 2013 for whom key demographic and medical history data were available | Not reported | RVF | 16 surgeries | Mucosal flap procedure, seton | Critical |
Milito, 2019 [18] | Italy, University Hospital of Tor Vergata, Rome | Women with CD who underwent surgery for an RVF performed by the same senior surgeon at a tertiary center | Not reported | RVF | 43 RVFs | Surgical procedures for RVF (surgical approaches included drainage and seton, rectal advancement flap, vaginal advancement flap, transperineal approach using porcine dermal matrix, and Martius flap) | No information |
Narang, 2016 [19] | USAd | All women who underwent RVF repair from July 1997 to June 2013 at two major tertiary referral centers Women who had recurrent symptoms at the time of the telephone survey but who had not visited their surgeon for full evaluation | Patients who did not agree to participate in the telephone follow-up survey or could not be reached | RVF | 99 RVFs | Episioproctotomy, muscle interposition (including GMT and Martius flap), placement of biological plug and fibrin glue, rectal-advancement flap, sphincteroplasty, and transvaginal repair | Serious |
Oakley, 2015 [20] | USAe | Possible cases of RVFs identified using ICD-9 codes of female genital digestive tract fistula July 2006–June 2011. Outpatient records with relevant ICD codesf | Charts with missing data for diagnosis or management | RVF | 106 RVFs 50 AVFs 20 unspecified RVFs or AVFs | N/A | Serious |
Park, 2019 [21] | USA, Olmsted Medical Center, Mayo Medical Center ,Rochester MN | Women diagnosed with CD from 1970 to 2010 | Not reported | RVF AVF | 13 RVFs or AVFs | N/A | Low |
Pinto, 2010 [22] | USAg | Women who underwent RVF repairs from January 1988 to May 2008 and who were surgically treated for AVFs and pouch vaginal fistulas | Patients with a rectourethral or anoperineal fistula; treated with only a diverting stoma; had < 3 months’ follow-up time; had a history of proctectomy or Hartmann procedure | RVF | 45 of 125 RVFs were CD related | Endorectal advancement flap, GMT, transvaginal approach, transperineal approach | Moderate |
Sapci, 2019 [23] | USA, surgical center not specified | Women diagnosed with CD who underwent surgery for RVF between 2010 and 2017 | Surgery without intent to close the fistula; < 6 months’ follow-up; inadequate follow-up to verify fistula status | RVF | 19 RVFs | Procedures to definitively close RVF: transanal advancement flap, transanal repair with tissue interposition (Martius or gracilis flap), episioproctotomy, fistulotomy, CAA, fistula plug | Moderate |
Schloericke, 2017 [24] | Germany, Department of Surgery, University of Schleswig–Holstein, Campus Luebeck and Department of Surgery, WKK Heide | Women who underwent treatment for AVF or RVF in the period January 2000 to September 2016 | Not reported | RVF | 58 RVFs | Non-resective procedures (transrectal/transvaginal omentoplasty or closure); resective procedures (low anterior resection, subtotal colectomy, proctectomy, pelvic exenteration, double-barrel sigmoidostomy) | Moderate |
Schwartz, 2019 [25] | USA | Cases of CD (≤ 1 claim of CD-related ICD-9 code in recent 5-year history) identified through December 31, 2014 with codes for fistulizing disease (identified by ICD-9 and surgical codes) in the Truven Health MarketScan database | Not reported | RVF | N/A | N/A | Moderate |
AVF anovaginal fistulas, CAA coloanal anastomosis, CD Crohn’s disease, ClinRO clinician-reported outcome, CRA colorectal anastomosis, ECF entero-cutaneous fistula, GMT gracilis muscle transposition, IBD inflammatory bowel disease, IBDSL Inflammatory Bowel Disease South Limburg Cohort, ICD International Classification of Diseases, ICD-9 International Classification of Diseases, ninth revision, N/A not applicable, PRO patient-reported outcome, ROBINS-I Risk Of Bias In Non-randomised Studies of Interventions, RVF rectovaginal fistula, SLR systematic literature review |
aSurgical center not specified, but authors affiliated with Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH |
bSurgical center not specified, but authors affiliated with Division of Colon and Rectal Surgery, Department of Surgery, University of Minnesota, Minneapolis, MN |
cComplex fistulas were defined as deep trans-sphincteric fistulas, fistulas with extensions of the primary track or associated abscess, fistulas associated with CD, anovaginal fistulas, and horseshoe fistulas |
dDepartment of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL and Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH |
eTwelve academic sites affiliated with female pelvic medicine and reconstructive surgery fellowship programs in the USA |
fSelected ICD codes included 565.1 (fistula, anal); 596.1 (intestine-vesical fistula); 596.2 (vesical fistula, not elsewhere classified); 619.0 (urinary-genital tract fistula, female); 619.1 (digestive-genital tract fistula, female); 619.2 (genital tract-skin fistula, female); 619.8 (other specified fistula involving female genital tract); 619.9 (unspecified fistula involving female genital tract) |
gSurgical center not specified, but authors affiliated with the Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL and Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH |
Most studies (n = 14) were retrospective cohort studies or case series that met the review definition for cohort studies [9, 14, 15, 10, 16–25]. The SLR also included one retrospective, unmatched case-control study [26] and one prospective cohort/registry study [27]. Two of the retrospective studies [14, 19] included prospective follow-up data collection (e.g., via telephone). All but two of the included reports [27, 25] came from either single- or multi-site, clinic-based studies, most often from surgical centers.
Two of the papers were identified as having a low risk of bias, and 10 papers had a moderate risk of bias. Serious or critical risk of bias was identified in three papers [26, 19, 20]. Risk of bias could not be determined in one source owing to lack of information in a published poster abstract [18] (Table 1).
Incidence and Prevalence
Three of the 16 included papers provided population-based estimates of RVF incidence or prevalence (Table 2). A study of a population-based inflammatory bowel disease cohort in the well defined South Limburg area of the Netherlands from 1991‒2014 reported that 17 of 728 female patients with CD (2.3%) had RVF [27]. A large, claims-based study conducted in the Truven Health MarketScan database by Schwartz et al. (2019) identified cases of CD with codes for fistulizing disease and estimated that > 6000 women were affected by RVF in the USA [25]. It should be noted that this study had a limited follow-up period and used International Classification of Diseases codes that may have poor validity in this area.
Table 2
Incidence and prevalence of Crohn’s-related RVFs and AVFs: key findings and commentary (n = 3 studies)
Author, year | Study/base population | Incidence | Prevalence |
Göttgens, 2017 [27] | • All adult patients with CD in the IBD South Limburg cohort. Since 1991, this cohort has included incident adult IBD cases in the South Limburg area of the Netherlands • Represents > 93% of all eligible patients in the region • Mean (SD) age at CD diagnosis = 37.7 (15.9) years • n = 1162 patients with CD; 728 female • Netherlands (CD diagnosis during 1991–2011, follow-up until 2014) | Overall cumulative probability of developing RVF among female patients with CD: • 0.7% after 1 year • 1.7% after 5 years • 3.1% after 10 years Cumulative 10-year probability of developing RVF among female patients with CD: • 1.7% for patients diagnosed with CD during 1999–2011 • 5.7% for patients diagnosed with CD during 1991–1998 | 2.3% (17/728; calculated value) among female patients with CD |
Schwartz, 2019 [25] | • Cases of CD with codes for fistulizing disease (Truven Health MarketScan database) • Age not reported • n = 73,878 (95% CI: 72,203–75,553) for 2014 • n = 75,666 (95% CI: 73,950–77,382) for 2017 • USA (data up to 2014) | Not reported | 2014 prevalence = 6064 (95% CI: 5656–6472) 2017 projected prevalence = 6211 (95% CI: 5793–6629) |
Park, 2019 [21] | • Patients with a CD diagnosis (Rochester Epidemiology Project medical records linkage system; health records of the residents of Olmsted County from Mayo Medical Center and Olmsted Medical Center) • Pediatric: 14.3%a (59/414) • Adult: 85.7%a (355/414) • n = 414 patients with CD • USA (CD diagnosis 1970–2010. Records reviewed until June 30, 2016) | Not reported | 3.1% (13/414) of patients diagnosed with CD between 1970 and 2010 had ≥ 1 RVF or AVF episode, January 1, 1970–June 30, 2016 |
AVF anovaginal fistula, CD Crohn’s disease, CI confidence interval, IBD inflammatory bowel disease, RVF rectovaginal fistula, SD standard deviation |
aCalculated value |
Schwartz et al. (2019) conducted their database analysis to support findings from an SLR. Their SLR reported only one study which the authors used to estimate the prevalence of patients with CD who had 1 (65.4%), 2 (19.2%), 3 (8.2%), 4 (4.5%), and 5 (2.7%) episodes of Crohn’s-related RVF. The median duration of fistula episodes for patients with 1, 2, 3, 4, and 5 episodes was 2.2, 7.1, 12.1, 17.1, and 22.0 years, respectively. The weighted average of medians of the duration of fistulizing CD was 5.1 years [25].
A study using data from the Rochester Epidemiology Project found that 3.1% of patients (13/414) diagnosed with CD between 1970 and 2010 had at least one RVF or AVF episode [21]. The South Limburg study estimated the overall cumulative probability of developing an RVF among female patients as 0.7% after 1 year, 1.7% after 5 years, and 3.1% after 10 years from CD diagnosis. The cumulative 10-year probability of developing an RVF among female patients with CD was 1.7% for patients diagnosed with CD between 1999 and 2011 (down from 5.7% for diagnosis between 1991 and 1998, which is prior to the introduction of anti-tumor necrosis factor agents [anti-TNFs]) [27].
No studies of AVF incidence or prevalence were identified. However, it should be noted that the terminology around fistula classification is not completely standardized. Of specific relevance to the current SLR is the interchangeable use of the terms AVF and ‘low RVF’ [28]. Studies do not always specify whether the RVFs described in their results include ‘low RVF’ (i.e., AVF).
Treatment Patterns
Treatment patterns in this context broadly refers to surgical procedures, medications, and conservative treatment including dietary modifications. It is known that RVF and AVF require substantial treatment; however, the SLR did not identify any population-based studies addressing treatment patterns in these conditions. The current SLR includes 12 (non-population-based) studies that address treatment patterns by fistula type.
The sheer number of preceding interventions and repeat interventions per patient described in the included studies, along with ineffective treatments leading patients to try alternative treatments and procedures, are indicative of a high burden of disease. It is important to note that many of the studies identified through this SLR are clinic or hospital based and provide a snapshot of treatment patterns at that institution at the time of study. Similarly, clinic and hospital studies generally have limited numbers of patients and aim to compare one intervention versus another intervention, rather than providing a broad picture of treatment patterns for all patients with the condition of interest. While the focus of this paper is the patient burden of RVF/AVF, the underlying burden of CD management including medications and surgeries is substantial.
Seven of 12 treatment pattern studies reported that patients had or required additional procedures before and/or after the intervention of interest, demonstrating a substantial treatment burden. It was frequently reported that patients had prior surgeries, such as anorectal surgery and fistula repair. For example, in a hospital-based study of 51 consecutive patients with CD who were undergoing treatment for RVF during 1998–2005, 40% of patients had previous anorectal surgery for CD. The median number of previous RVF surgical repairs in the group was 2–3, depending on the intervention group [15].
Six studies reported patients having other prior surgical interventions by fistula type, although some studies did not indicate whether the procedures were for the treatment of fistulas or the underlying CD. Procedures included seton drainage, diverting stoma creation, fistula plug, flap repair, fistulotomy, fistulectomy, fibrin glue, diverticulectomy, hemorrhoidectomy, hysterectomy, and sphincteroplasty [14–16, 26, 19, 23]. It should be noted that there is no single standard surgery for patients with AVF/RVF. Surgery of choice is dependent on location of fistula, severity, prior surgeries, degree of incontinence, and the surgeon’s clinical assessment and views on specific techniques (see Table 3).
Table 3
Studies providing information on treatment patterns (n = 12 studies)
Author, year | Baseline operations | Distribution of surgeries of interest | Surgery for failures/recurrence during follow-up | Immunosuppressive agents | Antibacterial agents |
Corte, 2015 [9] | Not reported by fistula type | 160 procedures in 34 patients with CD-related RVF Specific number for each procedure not reported by fistula type | Not reported by fistula type | Pre-operative: Investigators routinely propose anti-TNF therapy prior to surgery in patients with CD Post-operative: Not reported | Pre-operative: Not reported Post-operative: Not reported |
El-Gazzaz, 2010 [14] | Overall (n = 65) Seton: 32.3%a (21/65) Stoma: 60.0%a (39/65) Healed group (n = 30) Seton: 40.0%a (12/30) Stoma: 66.7%a (20/30) Unhealed group (n = 35) Seton: 25.7%a (9/35) Stoma: 54.3%a (19/35) | Overall Mucosal advancement flaps: 72.3% (47/65) Episioproctotomy: 12.3% (8/65) Proctectomy and pull-through procedure with coloanal anastomosis: 10.8% (7/65) Fibrin glue: 3.1% (2/65) Fistula plug placement: 1.5% (1/65) 27.7%a (18/65) of patients received > 3 repairs Median (range) number of repairs: Healed group: 2 (1–5) Unhealed group: 2 (1–8) p = 0.5 Median (IQR) interval from last repair to current, months: Healed group: 7.6 (4.1–11.1) Unhealed group: 9.7 (4.9–41.5) p = 0.1 Median (IQR) interval from seton to current repair, months: Healed group: 7.3 (5–8.9) Unhealed group: 4.2 (3.6–8.2) p = 0.5 Median (IQR) interval from stoma to current repair, months: Healed group: 5.7 (0.6–7.8) Unhealed group: 8 (0.9–22.9) p = 0.1 | Not reported | Pre-operative: Immunomodulator use (infliximab, adalimumab, 6-mercaptopurine, and azathioprine within the 3 months prior to surgery): 40.0%a (26/65) Steroids: 30.8%a (20/65) Post-operative: Not reported | Pre-operative: Not reported Post-operative: Not reported |
Gaertner, 2011 [15] | 1. Previously received medical therapy: 94%a (48/51) 2. Among patients who received surgery only (n = 25): - Previous RVF surgical repairs (median): 3 - Previous bowel resection for CD: 56% (14a/25) - Previous anorectal surgery for CD: 40% (10a/25) 3. Among patients who received surgery + infliximab (n = 26): - Previous RVF surgical repairs (median): 2 - Previous bowel resection for CD: 42% (11a/26) - Previous anorectal surgery for CD: 50% (13a/26) 4. Pre-operative fecal diversion: 19.6% (10/51) - 7 had undergone ileostomy - 3 had undergone colostomy | 1. Total (n = 51 patients, 65 procedures): 54%a (35/65) seton drainage 12%a (8/65) advancement flap 12%a (8/65) fibrin glue injection 9%a (6/65) transperineal repair 6%a (4/65) collagen plug placement 6%a (4/65) bulbocavernosus (Martius) flap 2. In the surgery only group (n = 25 patients, 30 procedures): 60% (18/30) seton drainage 7%a (2/30) advancement flap 20% (6/30) fibrin glue injection 13%a (4/30) transperineal repair 0% (0/30) collagen plug placement 0% (0/30 bulbocavernosus (Martius) flap 3. In the surgery + infliximab group (n = 26 patients, 35 procedures): 49% (17/35) seton drainage 17% (6/35) advancement flap 6% (2/35) fibrin glue injection 6% (2/35) transperineal repair 11% (4/35) collagen plug placement 11% (4/35) bulbocavernosus (Martius) flap Note: a patient might have received > 1 surgery | Of the 9 patients who did not heal: - Seton insertion: 33%a (3/9) - No seton insertion: 67%a (6/9) 27% (14/51) patients eventually required proctectomy (n = 9 treated by surgery alone and n = 5 treated by surgery + infliximab) | Pre-operative: 1. In the surgery + infliximab group (n = 26): 100% received preoperative infliximab of 5 mg/kg at 0, 2, and 6 weeks (mean of 3.6 [range, 3– 6] infusions) and were also taking 6-mercaptopurine or azathioprine 2. In the surgery only group (who did not receive infliximab) (n = 25): 23% (5/25c) 5-ASA derivative 9% (2/25c) azulfidine 64% (14/25c) prednisone 9% (2/25c) azathioprine 5% (1/25c) methotrexate 50% (11/25c) 6-mercaptopurine Post-operative: Not reported | Pre-operative: In the operation only group (who did not receive infliximab) (n = 25), as reported by the authors: 73% (n = 16) metronidazole 50% (n = 11) ciprofloxacin Peri-operative short-course antibiotics were given to 78.4%a (40/51) patients; assumed prophylactic Post-operative: Not reported |
Göttgens, 2017 [27] | Not reported by fistula type | Not reported by fistula type | Not reported by fistula type | Not reported with respect to surgery Exposure to immunomodulator or anti-TNFα therapy at any time prior to diagnosis of RVF: 1991–1998: 70% (7/10) 1999–2011: 60% (3/5) | Pre-operative: Not reported by fistula type Post-operative: Not reported by fistula type |
Jarrar, 2011 [16] | All patients underwent initial seton drainage and then flap repair ≥ 6 weeks later Other prior operations not reported by fistula type | Transanal endorectal advancement flap repair: 100% Note: if the fistula track was long it was drained with a mushroom catheter that was removed 10 days later. If the track was short the external opening was opened widely | Crohn’s AVF: n = 7 received 2nd flap n = 3 received 3rd flap n = 1 diverted Cryptoglandular perianal: n = 7 received 2nd flap n = 6 received 3rd flap n = 0 diverted Cryptoglandular anovaginal: n = 1 received 2nd flap n = 2 received 3rd flap n = 0 diverted | Pre-operative: Not reported Post-operative: Not reported | Pre-operative: Stated within 24 h prior to surgery and specified as prophylactic Post-operative: - Intravenous antibiotics continued post-surgery until discharge; unclear whether prophylactic - Oral antibiotics prescribed for 1 week |
Korsun, 2019b [17] | Not reported by fistula type | Not reported by fistula type | GMT: 100% | Peri-operatived: RVFs (n = 22 patients, including a patient with pouch and RVF) - Short-chain fatty acid: 4.5%a (1/22) - Enema: 4.5%a (1/22) - Azathioprine: 22.7%a (5/22) - Steroids: 22.7%a (5/22) - Colifoam: 4.5%a (1/22) - Mercaptopurine: 9.1%a (2/22) - Adalimumab: 9.1%a (2/22) - MTX: 4.5%a (1/22) - Sulfasalazine: 9.1%a (2/22) - None: 45.5%a (10/22) AVFs (n = 2 patients) - Azathioprine, steroids, mesalazine foam: 50%a (1/2) - None: 50%a (1/2) Medication before GMT: RVFs (n = 22 patients, including a patient with pouch and RVF) - Steroids: 9.1%a (2/22) - Azathioprine: 13.6%a (3/22) - Adalimumab: 9.1%a (2/22) - Mercaptopurine: 9.1%a (2/22) - Infliximab: 4.5%a (1/22) - Sulfasalazine: 4.5%a (1/22) - Mesalazine: 4.5%a (1/22) - None: 4.5%a (1/22) - Unknown: 59.1%a (13/22) AVFs (n = 2 patients) - Unknown: 100.0%a (2/2) Medication after GMT: RVFs (n = 22 patients, including a patient with pouch and RVF) - Mesalazine foam: 4.5%a (1/22) - Steroids: 27.3%a (6/22) - Azathioprine: 27.3%a (6/22) - Adalimumab: 9.1%a (2/22) - Sulfasalazine suppository/ sulfasalazine: 9.1%a (2/22) - MTX: 4.5%a (1/22) - Golimumab: 4.5%a (1/22) - Mercaptopurine: 4.5%a (1/22) - Unknown: 27.3%a (6/22) - None: 22.7%a (5/22) AVFs (n = 2 patients) - None: 50.0%a (1/2) - Azathioprine: 50.0%a (1/2) ≤ 1 medication per patient | Pre-operative: 100% received antibiotic (cefuroxime und metronidazole) 24 h prior to surgery—specified as prophylactic Post-operative: Not reported |
Manne, 2016b [26] | Past RVF surgery: - Cases: 50% (8/16) - Controls: 43% (20/47) | Proportion of patients who underwent mucosal flap procedure: - Cases: 88% - Controls: 12% Proportion of patients who underwent seton: - Cases: 13% - Controls: 77% Note: numbers for calculation not reported | Not reported | Pre-operative steroid use (timing prior to surgery unclear) - Cases: 25% (4/16) - Controls: 21% (10/47) Azathioprine/6-mercaptopurine use - Cases: 6% (1/16) - Controls: 15% (7/47) Biologic use: - Cases: 44% (7/16) - Controls: 62% (29/47) MTX use: - Cases: 6% (1/16) - Controls: 6% (3/47) | Pre-operative: Not reported Post-operative: Not reported |
Narang, 2016 [19] | 1. Had a seton before undergoing an attempted definitive surgical procedure: - Yes: 43.4% (43/99) - No: 56.6% (56/99) 2. Had a diverting stoma at the time of surgical repair: - Yes: 36.3% (36/99) - No: 63.6% (63/99) | Transrectal approach with endorectal advancement flap: 59.5%c (59/99) Transvaginal repair: 14.1%c (14/99) Muscle interposition: 14.1%c (14/99) Martius or groin flaps: 9.6%c (9/99) GMT: 5.3%c (5/99) Episioproctotomy: 6.4%c (6/99) Overlapping sphincteroplasty: 3.2%c (3/99) Fibrin glue placement: 2.1%c (2/99) Biological plug insertion: 1.1%c (1/99) Note: reported calculations could not be replicated | Not reported | At baseline: Steroids: 57.6%a (57/99) Infliximab: 48.5%a (48/99) Adalimumab: 20.2%a (20/99) Azathioprine: 4.0%a (4/99) 6-mercaptopurine: 4.0%a (4/99) Follow-up: Not reported | Pre-operative: Not reported Post-operative: Not reported |
Oakley, 2015 [20] | Not reported by fistula type | Patients with Crohn’s RVF: 20%a (4/20) patients received initial expectant therapy 80%a (16/20) patients received initial surgery | Not reported | Pre-operative: Not reported by fistula type Post-operative: Not reported by fistula type | Pre-operative: Not reported by fistula type Post-operative: Not reported by fistula type |
Pinto, 2010 [22] | Not reported by fistula type | In the 45 patients with CD, 80 procedures were performed: - Endorectal advancement flap: 47.5% (38/80) - GMT: 7.5% (6/80) - Transvaginal repair: 3.8% (3/80) - Transperineal repair: 3.8% (3/80) - Others: 37.5% (30/80) | Not reported | Pre-operative: Not reported by fistula type Post-operative: Not reported | Pre-operative: Not reported Post-operative: Not reported |
Sapci, 2019 [23] | 1. Previous surgery to close fistula: 57.9%a (11/19) 2. History of ≥ 2 surgeries to close fistula: 52.6% (10a/19) | Transanal advancement flap: 42.1% (8/19) Transanal repair with tissue interposition (Martius or gracilis flap): 15.8% (3/19) Episioproctotomy: 10.5% (2/19) Fistulotomy: 10.5% (2/19) Coloanal anastomosis: 10.5% (2/19) Fistula plug: 10.5% (2/19) Active smoker: 42.1% (8/19) | Not reported | Pre-operative: Not reported Post-operative: Not reported | Pre-operative: Not reported Post-operative: Not reported |
Schloericke, 2017 [24] | Recurrent cases included, but exact numbers and previous treatments are unclear | Patients with CD received resective surgical treatment only: - Low anterior resection: n = 6 - Subtotal colectomy: n = 3 (all patients indicated for this surgery based on presence of toxic megacolon) - Proctectomy: n = 1 - Pelvic exenteration: n = 1 Note: total number of patients with CD = 15, but only 11 surgeries reported | Proctectomy was performed in 1 case of recurrent fistulas in CD that led to severe sepsis | Not reported | Not reported |
5-ASA aminosalicylate, AVF anovaginal fistula, CD Crohn’s disease, GMT gracilis muscle transposition, IQR interquartile range, MTX methotrexate, RVF rectovaginal fistula, TNF tumor necrosis factor |
aCalculated value |
bMedication information provided from corresponding author via email |
cNumbers and percentages are reported as they were provided in the original article |
dNumbers provided via correspondence from author in response to request for clarification |
Another important aspect of treatment burden is the need for additional surgeries following the interventions of interest in the published studies. For example, 14 of the 51 patients (27%) described in the study above [15] eventually required proctectomies. In another study, seven of 21 patients with AVF who underwent transanal endorectal advancement flap repair received a second flap, three received a third flap, and one was diverted [16].
In addition to the surgical and procedural burden, this SLR indicated that patients with RVF/AVF report a heavy medication burden for both CD and fistula. For example, 94% of patients (48/51) who underwent treatment for RVF during 1998–2005 had received previous medication therapy, though it is unclear whether this was therapy for CD or fistula, specifically [15]. Seven of the 12 studies reporting on treatment patterns provided details on prior use of medications to manage CD and/or fistula. In a hospital-based study of 65 women who underwent surgery to close a RVF, 40% (26/65) had taken immunomodulators and 30.8% (20/65) had taken steroids within 3 months prior to surgery [14]. Reported medications include anti-TNF biologics, corticosteroids, azathioprine, methotrexate, 6 mercaptopurine, and antibiotics [9, 14, 15, 27, 16, 17, 26, 19] (Table 3).
In addition to these surgical and medical treatments, other treatments for CD and RVF/AVF may include conservative management techniques, such as local wound debridement, low residue diets, and sitz baths, although the data for these approaches are not enumerated in the literature [20].
Clinical Outcomes
Eleven studies included data on clinical outcomes for treatments of RVF/AVF (Table 4). The variability in treatments, study design, and description of outcomes further demonstrates the complexity of the clinical situation. As with the classification of the fistula overall (e.g., AVF vs ‘low RVF’), investigators use varying terminology, with or without clear definitions, to describe outcomes of interest (e.g., healing, closure, response).
Table 4
Interventions and success and failure rates in published studies (n = 11 studies)
Author, year | RVF/AVF sample size | Intervention(s) | Median follow-up duration, months (range) | Key outcome definitions | Success and failure rates | Post-operative infection rates |
Corte, 2015 [9] | 79 RVFs | Conservative procedures: seton drainage, vaginal advancement flap, rectal advancement flap, diverting stoma only, fistula plug, fibrin glue Major procedures: GMT, biomesh interposition, standard CAA or CRA, delayed CAA, abdominoperineal excision | 33.1 (4–190); success ascertained at 3 months | Success: absence of any vaginal discharge of feces, flatus, or mucous discharge during ≥ 3 months after the last procedure AND absence of stoma. Patients who underwent a stoma performed after RVF healing for a non-RVF-related condition were considered as success | Success rate: 14.4% (23/160) in RVFs with CD etiology (160 procedures among 34 patients with CD-related RVF) | Not reported |
El-Gazzaz, 2010 [14] | 65 RVFs | Advancement flap, coloanal anastomosis, episioproctomy, fibrin glue or plug | 44.6 (IQR: 13.1–79.1) | Healing (closed RVF): all pre-operative symptoms attributable to the fistula resolved at the time of follow-up and no fistula detected by physical examination at the last office visit | Healing rate, by type of current surgery: Mucosal advancement flap: 42.6% (20/47) CAA: 57.1% (4/7) Episioproctotomy: 71.4% (5/8)b Fibrin glue: 50.0% (1/2) Plug: 0% (0/1) | Not reported |
Gaertner, 2011 [15] | 51 RVFs | Operative treatment, operative treatment + infliximab | 38.6 (mean); (3–204) | Completely healed: no clinical evidence of fistula Minimally symptomatic: seton placement with minimal drainage and/or infliximab dependence Failure: persistent or recurrent symptomatic fistula, diverting procedure or proctectomy | | Surgery only (n = 25) | Surgery + infliximab (n = 26) | Completely healed | 24% (6/25) | 46% (12/26) | Minimally symptomatic | 20% (5/25) | 15% (4/26) | Healing rates: ‘completely healed’ + ‘minimally symptomatic’ | 44% (11/25) | 62% (16/26) | Fistula closure | Not reported | 54%a (14/26) | Healing rates by operative approach (numbers for calculation not reported) | Surgery only (n = 25) | Surgery + infliximab (n = 26) | Transperianal repair (n = 6) | 100% | 50% | Seton drainage (n = 35) | 33% | 65% | Advancement flap (n = 8) | 50% | 0% | Fibrin glue (n = 8) | 0% | 0% | Martius flap (n = 4) | NA | 75% | Collagen plug (n = 4) | NA | 50% | | Not reported |
Haennig, 2015 [10] | 12 RVFs | Seton drainage and associated treatment, infliximab, external drainage, fibrin glue, advancement flap, fistulotomy Other treatments (external drainage + infliximab, fistulotomy + infliximab, advancement flap + infliximab, infliximab [monotherapy], external drainage, bowel diversion) | 64 (2–263) | Interval to closure: closure not defined | RVF: time interval to closure = 30.6 months vs 12 months for anal fistulas, p = 0.02 RVF not significantly correlated with relapse (p = 0.24) | Not reported |
Jarrar, 2011 [16] | 21 AVFs | Transanal endorectal advancement flap repair | Follow-up calls at 7 ± 3 years | Healing: not defined | Healing rate, after 1st flap: 41.7% (5/12) Healing rate, after 2nd flap: 42.9% (3/7) Healing rate, after 3rd flap: 66.7% (2/3) Healing rate, overall: 83.3% (10/12) | Not reported by fistula type |
Korsun, 2019 [17] | 21 RVFs 2 AVFs | GMT | 47 (mean); (1–144) | Complete closure of fistula by 1st follow-up (~ 3 months post-operatively) without additional follow-up operations | Fistula closure rate: RVF: 71% (15a/21); including 1 patient with an abscess after GMT without fistula proof AVF: 50% (1a/2) Stoma closure rate: RVF: 55% (numerator unclear); 1 patient operated without stoma and 1 patient opting against stoma closure after fistula closure AVF: 50% (1a/2) | 4.8%a (1/21) patient with RVF had an abscess after the surgery without fistula proof |
Milito, 2019 [18] | 43 RVFs | Surgical approaches included drainage and seton, rectal advancement flap, vaginal advancement flap, transperineal approach using porcine dermal matrix, and Martius flap | 18 | Complete healing, healing rate and failure rate: not defined | Median time to ‘complete healing’: 6 months (range: 2–11 months) Healing rate: 81% (numbers for calculation not reported) Failure rate: 19% (numbers for calculation not reported) | Not reported |
Narang, 2016 [19] | 99 RVFs | Episioproctotomy, muscle interposition (including GMT and Martius flap), placement of biological plug and fibrin glue, rectal-advancement flap, sphincteroplasty, and transvaginal repair | 39.1 (mean) ± 52.2 (SD) | Healing: not defined Failure to heal: persistence of symptoms that were compatible with the initial symptoms before surgical repair or current fecal drainage through the vagina | Overall healing: 63.7% (63/99)b Healing in patients with prior seton: 55.8% (24/43) Healing in patients with prior stoma: 52.8% (19/36) Healing in patients with systemic steroid treatment within 30 days of surgery: 61.4% (35/57) Healing in patients with biologic therapy within 30 days of surgery: 63.2% (43/68)* *Note: numerator does not match the total healing count for infliximab and adalimumab, below Healing in patients with CD and obstetric injury: 74.0% (26/35)b Healing in patients with steroids within 30 days of surgery: 61.4% (35/57) Healing in patients with infliximab within 30 days of surgery: 47.9% (23/48) Healing in patients with adalimumab within 30 days of surgery: 55.0% (11/20) | 1 patient (1%a, 1/99) had urinary tract infection < 30 days after surgery |
Pinto, 2010 [22] | 45 of 125 RVFs were CD related | Endorectal advancement flap, GMT, transvaginal approach, transperineal approach | 16.3 (mean) | Success: not defined Recurrence: persistence of symptoms compatible with the initial complaints and confirmed by physical examination or supplemental studies | Initial success rate: 44.2% (34/77 procedures) Recurrence rate: 55.8% (43/77 procedures) Eventual success rate (those who healed either initially or after recurrence): 78% (numbers for calculation not reported) after an average of 1.8 procedures | Not reported by fistula type |
Sapci, 2019 [23] | 19 RVFs | Transanal advancement flap, transanal repair with tissue interposition (Martius or gracilis flap), episioproctotomy, fistulotomy, CAA, fistula plug | 29.6 (mean) | Success: no symptoms ≥ 6 months after definitive repair and/or stoma closure | Overall healing rate: 63% (12/19) Success rate in patients who received a biologic within 3 months of surgery: 50% (4/8) Successful closure by procedures: Transanal advancement flap: 50% (4/8) Transanal repair with tissue interposition (Martius or gracilis flap): 67% (2/3) Episioproctotomy: 100% (2/2) Fistulotomy: 100% (2/2) CAA: 100% (2/2) Fistula plug: 0% (0/2) Active smoker: 75% (6/8) Patients with peri-operative diversion had higher rates of success compared with no diversion group (66% vs 57%, p = 1)—numbers for calculation not reported | Not reported |
Schloericke, 2017 [24] | 58 RVFs | Non-resective procedures (transrectal/transvaginal omentoplasty or closure) Resective procedures (low anterior resection, subtotal colectomy, proctectomy, pelvic exenteration, double-barrel sigmoidostomy) | 13 (3–36) | Recurrence: not defined | Complicated recurrence due to development of multiple perianal fistulas with severe sepsis: 13.3% (2/15) | In 13.3%a (2/15) patients with CD, recurrence was complicated because of the development of multiple perianal fistulas with severe sepsis which led to emergency abdominoperineal excision of the rectum in one patient |
AVF anovaginal fistula, CAA coloanal anastomosis, CD Crohn’s disease, CRA colorectal anastomosis, GMT gracilis muscle transposition, IQR interquartile range, RVF rectovaginal fistula |
aCalculated value |
bNumbers and percentages are reported as they were provided in the original article |
Nevertheless, most studies include some assessment of success of the surgical procedure. For example, Haennig et al. (2015) identified the median ‘interval to fistula closure’ after seton drainage and infliximab treatment in 12 patients with RVF as 30.6 months [10]. Milito et al. (2019) measured median time to ‘complete healing’ in 43 patients with RVF as 6 months (range: 2–11 months) [18]. Other studies measured the rate of closure or healing, some by surgical type and some across surgical types. Of the nine studies that reported healing/success/closure across multiple surgical types, rates varied from 14.4–81% [9, 18], with seven ranging between 50% and 75% [14–19, 23]. Some of the variation may be explained by differences in study design, population characteristics, and surgical types included.
‘Recurrence rates’ were specifically reported in two studies and ranged from 13.3% (complicated recurrence due to development of multiple perianal fistulas with severe sepsis) to 55.8% across multiple procedures [22, 24]. Five studies reported post-operative infection rates; however, two [16, 22] did not report rates by fistula type. In the three studies that did report RVF/AVF-specific rates, 1–13.3% of patients experienced a post-operative infection, including one abscess [17], one urinary tract infection [19], and two cases of severe sepsis [24]. Further complicating interpretation of these results is the variance in median or mean follow-up duration which ranged from 13 months [24] to 7 years [16].
Patient-Reported Outcomes
One of the 16 included studies offered findings collected through PRO instruments. El-Gazzaz et al. (2010) analyzed quality of life (QoL) data from the 12-item Short-Form Health Survey, Fecal Incontinence Quality of Life (FIQL), and Female Sexual Function Index (FSFI) questionnaires administered at surgical follow-up visits. The authors report ‘modest’ scores in the PRO instruments. For example, patients’ mean scores on the FIQL ranged from 2.5 to 3.1 (out of 5, with lower scores indicating lower QoL) in each of the scored domains (lifestyle, coping, depression, and embarrassment). FSFI total scores averaged 17.3 ± 6.7 and 17.9 ± 9.4 (from a possible total of 36, with lower scores indicating worse functioning) in healed and unhealed women, respectively. The surveys showed no statistically significant differences in QoL or sexual function among healed versus unhealed patients, and the authors suggest this may be due to the underlying effects of CD regardless of its complications [14]. This study is limited by the questionnaire completion rate among patients (45%) and reporting bias(es) regarding potential reticence of patients to discuss the sensitive nature of sexual health topics. Although a logical component of the disease burden in this population and one that may be captured in studies of CD overall, little is known about sexual interest and satisfaction among women with RVF/AVF. Similarly, more studies are needed to determine overall QoL and other insights into the patient experience that could be captured uniquely through PRO instruments.
Healthcare Resource Utilization
None of the 16 studies reported HCRU among patients by fistula type. More studies are needed to determine the direct and indirect costs of RVF and AVF, particularly as they relate to healthcare visits, copays, prescriptions, ancillary care such as psychological support, missed days at work and/or school, and productivity loss.