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`Patent Owner, UCB Pharma GmbH — Exhi
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`it 2062 - 0056
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`it 2062 - 0057
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`
`

`
`deviation from Hardy-Weinberg Equilibrium for con-
`trols, or both cases and controls, highly suggestive
`either of genotyping error, or problems with popula-
`tion stratification. In addition to the high risk of bias
`introduced, these studies are all underpowered oth-
`er than for extremely large genetic effects, and in
`most cases fail to account for multiple comparisons
`in their primary analyses.
`
`Despite this multiplicity of methodological prob-
`lems. there remains tentative evidence of repli-
`cated effects for two different polymorphisms.
`The rs‘l 800012 polymorphism of collagen type I
`alphai (COLIA1). has been associated with a two-
`fold increased prevalence of stress incontinence
`in separate European populations [758,767]. The
`rs4994 polymorphism of the beta 3 adrenocep-
`tor (ADRB3) has been associated with almost 2.5
`fold increased risk of overactive bladder in sepa-
`rate studies of Japanese and Brazilian samples
`[30,31]. Other polymorphisms tested in more than
`one study include rs6313 in the 5—HT2A receptor,
`and rs1799750 in matrix metaI|oproteinase—1.
`In
`each case there are however inconsistent find-
`
`ings, with a high risk of genotyping error, and or
`population stratification.
`
`Candidate gene studies for prolapse are at an
`equally nascent stage. Here polymorphisms have
`been tested in COLIA1, COLSA1, LOX-L1, LAMC,
`lVlMPs1, 2, 3, 8, 9, 10, 11, TIMP1, TIMP3, ESFt,
`and PGR. In comparison to incontinence, investi-
`gators have used the POPQ system as standard.
`However, other methodological problems are com-
`mon. We again found many underpowered studies,
`frequent significant deviation from Hardy-Wein-
`berg Equilibrium, and many instances of failure
`to consider the impact of population stratification
`in samples. Although many of the primary studies
`report significant results, our reanalysis suggests
`that there are no consistently replicated associa-
`tions in any populations.
`
`With these disappointing results in mind we can
`consider findings from the first reported genome
`wide association study in this area. The discovery
`cohort comprised 115 familial cases of prolapse
`identified as having had surgical treatment (and fre-
`quently also stress or urgency incontinence treat-
`ment) with 2,976 controls. In the discovery cohort 6
`individual SNPs approached or exceeded genome
`wide significance (p<=5x10-8), but
`in Manhattan
`and Regional Association Plots no evidence was
`seen to support a wider associated locus. Corre-
`spondingly, after correction for multiple compari-
`sons none of the 6 SNPs (rs14553‘l‘1 rs1036819
`rs430794 rs802?7‘l4 rs1810636 rs2236479) were
`successfully replicated in a sample of 76 Dutch fa-
`milial cases. Given the failure of the candidate gene
`approach, genome-wide association studies are ur-
`gently needed, but will require much larger samples
`of cases for reliable identification of significant loci.
`
`VI. SUMMARY POINTS
`
`Family studies and twin studies have provided
`convincing evidence of genetic predisposition to
`incontinence and prolapse, with genetic variation
`contributing up to half of population phenotypic vari-
`ability in elderly women. Despite a large research
`effort, the candidate gene approach has not pro-
`duced consistent results. Only the rs18000‘l2 poly-
`morphism of collagen type I a|pha‘l (COLIAI), and
`the rs4994 polymorphism of the beta 3 adrenocep—
`tor (ADRB3) have been replicated. Despite an ur-
`gent need for genome-wide association studies to
`discover susceptibility genes for these conditions,
`initial results from the genome-wide approach have
`been fruitless. Future progress will
`likely be made
`through collaboration between large scale popula-
`tion based cohons phenotyped for these conditions.
`
`I. EPIDEMIOLOGY OF ANAL
`
`INCONTINENCE
`
`I. GENERAL COMMENTS AND
`DEFINITIONS
`
`Faecal Incontinence (Fl) is the involuntary loss of
`faeces — solid or liquid. Anal Incontinence (Al) in-
`cludes these events as well as the involuntary loss
`of flatus, which is felt by many patients to be an
`equally disabling disorder.
`
`The discussion below will therefore focus on the
`
`broader definition: Al. A third cause of soiling or
`embarrassment is anal mucoid seepage, a trou-
`bling condition that cannot be deferred by an able
`sphincter and intact cognition, most often caused
`by an organic colonic disease or dietary sensitiv-
`ity, and more rarely by faecal impaction. This is the
`loss of fluid, sometimes faeculent, often following a
`normal continent defaecation. This is an important
`condition to distinguish from other manifestations
`of incontinence because most authors that report
`very high prevalence rates of Al
`include leakage
`in their questionnaires and thus may include these
`individuals with this very common symptom. How-
`ever in these individuals there is often no detect-
`
`able sphincter abnormality [786]. It is not treatable
`by any of the standard therapies for incontinence of
`faeces: such as sphincter repair, neuromuscular re-
`education or even faecal diversion. It is in fact why
`we wear underclothes. Not really true for women.
`
`1. ASCERTAINMENT OF ANAL INCONTINENCE
`
`Older reports of Al prevalence have come from sin-
`gle institutions, and the patients described therein
`have been subject to referral bias when demograph-
`ics and aetiology are discussed. The accuracy of Al
`
`70
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0058
`
`

`
`prevalence estimates may also be diminished by dif-
`ficulty in ascertaining those figures due to the com-
`mon underreporting of Al and patients‘ reluctance
`to report symptoms or to seek treatment [787-788].
`It has been shown that women are more willing to
`report Al than men [789] In addition, the character
`(incontinence of solid faeces. diarrhoea. or flatus. or
`merely anal seepage) and frequency (daily versus
`episodic) of reported AI varies greatly in each report,
`and indeed between individuals. So, prevalence de-
`pends heavily on the definition of Al.
`
`The variation in prevalence of Al seen in a sampling
`of surveys in Table 21 further demonstrates how dif-
`ficult the ascertainment ofAl is. The border between
`
`occasional dyschezia which may be associated with
`minor illness. travel or diet and a disabling disease
`that requires intervention to return a patient to ac-
`ceptable function is not cleariy drawn. Many ques-
`tionnaires have been developed and ‘‘validated‘‘ for
`the detection of Al. at least three published since
`the last update of this book. No systematic review of
`these many questionnaires has yet to be published.
`The most insightful of prevalence studies has recent-
`ly been published from New Zealand [790]. The au-
`thors studied adults, not excluding those in custodial
`care. Acknowledging the difficulty in prevalence esti-
`mation, they used three different questionnaires: the
`first simply asking if the participant had incontinence
`and if they were troubled by it, the second a well
`known quantitative instrument and the third a qual-
`ity of life instrument specific to faecal incontinence.
`In the cohort examined there were those who were
`
`totally continent. those that exceeded thresholds in
`all three instruments and were incontinent and those
`
`who had positive responses on only one or two of the
`questionnaires (Figure 11). The authors surmised
`the two out of three positive responses constituted
`clinical Al, though the threshold for the quality of life
`instrument was very high (i.e. perhaps too sensitive).
`From Figure 11 it can be seen that the prevalence of
`Al varied from 12.6% to 26.8% for each individual in-
`
`strument, 4.6% were positive for all three and 13.2%
`were positive for two of three. which was the authors‘
`definition of Al.
`
`2. DATA SOURCES AND LEVEL OF EVIDENCE
`
`Since ICI 4 new studies were sought using Medline
`and EMBASE using the search terms faecal. faecal,
`anal,
`incontinence. epidemiology.
`In addition sys-
`tematic reviews were specifically sought in Medline.
`EMBASE and the Cochrane Library.
`
`ll. PREVALENCE
`
`the
`Because therapeutic interventions are not
`subject of this chapter. and so the epidemiology
`is descriptive and not derived from randomised
`clinical trials (aside from the antenatal intervention
`described below). the level of evidence will be at
`best 2. and the strongest evidence will come from
`systematic reviews in which there was a predefined
`search strategy and application of quality assess-
`ment tools that were designed specifically to mini-
`mize bias in referral or ascertainment.
`
`Table 21'. Popufafion-based Surveys of Prevalence of Anal’ incontinence
`N
`PREVALENCE
`COUNTRY (ref)
`POPULATION
`4 844
`1.9%
`U.K. [?8B]
`Community Service
`1 100
`11%. 6% to faeces. 60% are women
`France [808]
`All >45 years
`U.S.A. [806]
`Market mailing
`5 430
`7% soiling, 0.7% to faeces
`6 959
`2.2%. 63% women
`U,S.A. [789]
`Wisconsin households
`Australia [805]
`Household survey
`3 010
`6.8% in men. 10.9% in women. >age 15
`Germany [811]
`>18 years
`500
`4.4%-6.7% (by health)
`Australia [810]
`>18 years
`513
`11-20% (gender M>F)
`651
`1 1.3%
`Australia [482]
`>15 years
`New Zealand [814]
`>18 years old
`T1?
`8.1% for solid and higher for gas
`10 116
`1.4%
`UK. [815]
`>40 years
`549
`5.5%
`U.l<. [8161
`Postpartum women
`949
`3.1% solid, 25.5% flatus
`Canada [817]
`Postpartum women
`Denmark [818]
`Postpartum women
`1 726
`8.6% in past year. 0.6% to solid stool
`3 963
`6.9%. 2.3% to solid stool
`Nigeria [819]
`Gynecology patients
`450
`11.3%. 5.5% to solid stool
`United Arab Emirates [820]
`Women multips
`223
`3.5% flatus. 3% Fl
`Teenage females
`Canada [821]
`Czech Republic [822]
`Gynecology patients
`2 212
`5.6%. 4.4% in the community
`Japan [823]
`Cystectomy patients
`28
`60.7% post ureterosigmoidostomy
`364
`RR 1.3-4.5
`Sweden [824]
`Prostate cancer
`8 65?
`Increased risk
`Australia [8251
`Diabetics
`Holland [826]
`Women >60 years
`719
`4.2% to 16.9% with rising age
`328
`3.?% (M >F)
`USA. [827]
`>65 years at home
`Japan [828]
`>85 years at home
`1 405
`as-3.7% (by age).
`USA. [829]
`>50 years
`1440
`11.1—15.2%(F>M)
`2 818
`3%
`U.K. [830]
`>65 years at home
`Holland [831]
`>60 years
`3 345
`6%. (M = F)
`1 162
`54.4%
`Czech Republic [832]
`Nursing homes
`16 1?0
`47% Fl
`U.S.A. [333]
`Nursing homes
`44?
`46% Fl. 44% both UI and Fl
`Canada [834]
`Nursing homes
`France [835]
`>18 years
`1'13
`30% response rate. 11% gas.0.4% feces. Women>men.
`U.S.A. [836]
`Women >20 years
`2 800
`53% response rate. Median age onset 55 years.
`France [837]
`Women >50 years
`2 640
`85% response rate. 9.5% Fl. but includes leakage.
`USA [838]
`Women >25 years
`4 10
`337% response rate. 25% Al. Obesity.
`
`7!
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0059
`
`

`
`1. ADULTS
`
`In an effort to resolve the widely varying reported
`prevalence figures (Table 21) two systematic re-
`views of the published frequencies have been
`reported of community dwelling adults (above
`age 15 in the second). A summary frequency was
`not calculated in the first because of the marked
`
`clinical heterogeneity between reports. The three
`reports that the authors judged most free of po-
`tential biases had frequencies between 11% and
`15%, although only one of these three used a
`validated assessment instrument [791]_ The de-
`gree ofdisability present in these 11%-15% is not
`known, nor even if a portion of them had only
`anal seepage. These high prevalences were
`obtained in surveys that employed anonymous
`self-administered questionnaires, which may not
`allow objective confirmation of Al or assessment
`of degree of disability associated with Al. The
`second systematic review found a range of solid
`and liquid anal incontinence of 045.2%, with an
`average across both genders and all age groups
`of 4.3% [462]_ The prevalence in a more recent
`and rigorous study is discussed above under As-
`certainment [790].
`
`2. CHILDREN
`
`in children can be
`The reported prevalence of Al
`broadly divided into two facets:
`in those children
`born with congenital anomalies of the anus and rec-
`tum - either congenital aganglionosis (Hirschprung's
`Disease) or imperforate anus — and those children
`without congenital anomalies. Among those children
`
`and adults who were born with defects. despite sur-
`gical correction of the defect, life long defaecation
`difficulties are common, occurring in roughly half of
`affected children [792-794]. Problems with psycho-
`logical health and development because of the de-
`faecation disorder is also common in this group, as
`is a generally depressed quality of life [795]. These
`disorders are not horribly rare, occurring in 3 to 5
`per 10,000 live births [796].
`
`Among children without congenital defects of
`the anal canal. bowel control has been found to
`be complete in one Swiss cohort in 33% by age
`1 year. 75% by age two and 9?'% by age three.
`Nevertheless in this longitudinal study, a quarter
`of the boys and one tenth of the girls had a ma-
`jor period of incomplete bowel or bladder control
`between the ages of 6 and 18. At least annual en-
`copresis occurred in 2—3°/o of these children, boys
`more frequently than girls [797].
`In the Wisconsin
`Family Health Survey the prevalence of AI in chil-
`dren from the ages of 5 and 16 years was 12f1367
`(0.88%) with the gender distribution being 7 boys
`and 5 girls (Wisconsin Family Health Survey: un-
`published data). The common disorder for all chil-
`dren and then adults in this discussion is faecal
`retention with overflow.
`
`III. INCIDENCE
`
`Clinical trials have provided incidence data after a
`therapeutic intervention, but usually without a pre-
`liminary continence assessment. This is best seen
`in two Cochrane reviews of therapy for anal fissure
`
`
`
`
`bowel control
`
` "Do you feel you have a
`
`problem ?"
`
`
`
`Incontinence of liquid!
`solid stool 21/month
`(FISI)
`
`Quality of life
`Impairment lFIQLSl
`
`1 Shaded area = at least 2/3 of possible diagnostic measures
`
`Figure 17. Co-occurrence of fecal incontinence in each of 3 diagnostic measures. FiSl' = Fecal
`tinence Severirty index; FIOLS = Fecal incontinence Quality of Life Scale
`
`incon-
`
`72
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0060
`
`

`
`[T98-799]. AI incidence rates varied widely from 0%
`to 30%, to flatus only, and the duration was unspeci-
`fied in the trials. Medical therapy was less likely than
`surgery to cause Al (0.23, 0.02-2.1), and certain op-
`erations (anal stretch) were more likely to cause Al
`than others (sphincterotomy) (4.2, 1.9-9.4). None of
`these trials reported rigorous ascertainment of con-
`tinence before the onset of disease or therapy.
`
`IV. RISK FACTORS
`
`1.AGE
`
`Two systematic reviews have analyses of the asso-
`ciation of age and anal incontinence and found age
`to be the most significant of all assessed associa-
`tions [800-801].
`
`2. GENDER
`
`Most discussions of the aetiology of Al have been
`based upon the assumption that women, partic-
`ularly for individuals under the age of 65 years,
`are far more at risk for Al than men. Injury to the
`pudendal nerve or sphincter muscle from prior
`obstetric trauma is described as the primary risk
`factor [802—804], followed by irritable bowel syn-
`drome (a disease thought to be more prevalent
`in women) [805], and other aetiologies such as
`diabetes a distant third [B06]. Yet each population
`based-survey of the prevalence ofAl has shown a
`surprisingly high prevalence in males (Table 21)
`[788-789, 807-838].
`
`Of the two systematic reviews that looked specifi-
`cally at prevalence, only one assessed the role
`gender played and in that review gender was not
`associated with incontinence in any age group
`[800].
`In the search for this updated review, 26
`publications assessed prevalence of AI,
`two in
`both genders and 24 only in women. Clearly. aeti-
`ologies other than childbirth must be sought. This
`represents a rather gross imbalance in research
`on this topic.
`
`3. OBESITY
`
`Four reports have demonstrated an increased risk
`of Al in obese women, a Kaiser cohort, a cross sec-
`tional survey in a specialty clinic and two case con-
`trol studies [839—842]. One longitudinal study found
`a reduction in anal leakage (again not necessarily
`a direct correlate with incontinence) in women af-
`ter bariatric surgery and weight loss, though other
`factors including diet and activity change may have
`been responsible for the improvement [843].
`
`4. CHILDBIRTH AND MODE OF DELIVERY
`
`Another systematic review that looked only at post
`partum factors in prospective cohorts found that the
`only predictor of Al was 3rd-4th degree sphincter
`rupture during birth [845]. Three things are implied
`by the conclusion or the first review: first, that incon-
`tinence in men, children, of elderly onset (or even in
`middle aged women) and in nulliparous
`
`women, or women having Caesarean section has a
`completely different cause than in women who have
`ever delivered vaginally. There is scant epidemio-
`logical evidence that this is the case [846]. Second,
`it is implied that sphincter repair would be effective
`
`treatment for anal incontinence in almost all parous
`women. Yet repair of disrupted sphincter has less
`than a perfect track record. Even more important-
`ly, there is a reported rapid decay in function after
`repair that is far too great to be explained by age
`alone [847-854]. Third.
`if direct trauma to the anal
`sphincter (and not intra-pelvic nerves) were the ma-
`ior cause of anal incontinence, then Caesarean sec-
`tion should beeffective in preventing incontinence.
`However a systematic review has shown that this is
`not the case [801] (Figure 12). Twenty-one reports
`have been found eligible for inclusion in the review,
`encompassing 31,198 women having had 6,028
`Caesarean deliveries and 25,170 vaginal births as
`index events prior to anal continence assessment.
`Only one of these reports demonstrated a significant
`benefit of Caesarean section in the preservation of
`anal continence.
`In that report Al rates exceeded
`39% in both groups, suggesting a problem with as-
`certainment. The greater the Glkiallty of the report,
`the closer its Odds ration approached 1.0. Among
`the seven reports that passed all quality criteria (age
`adjustment, parity adjustment, no previous vaginal
`delivery in the Caesarean section group, continence
`assessment more than 4 months post partum) the
`odds ratio for faecal incontinence was 0.98 (0.79-
`1.21. Figure 12).
`In reports that allowed compari-
`son of vaginal delivery with elective Caesarean
`section there was also no significant difference in
`Al risk (OR=0.'/3; 0.52-1.03. Figure 13) There was
`no difference incontinence preservation in women
`have emergency versus elective Caesarean section
`(OR: 1.09; 0.89-1.34. Figure 14). Among the seven
`best studies, the NNT is 339,
`i_e. 339 Caesarean
`sections would have to be performed to prevent a
`single case of faecal incontinence. Pregnancy with
`delivery of any kind was found to be only a marginal
`risk factor for faecal incontinence (OR= 0.86; 0.73-
`1.0‘l. Figure 15) though there is significant statisti-
`cal heterogeneity in this analysis (p=0.05, l2=62%).
`In another publication increasing parity as an iso-
`lated risk factor does increase risk of Al [838].
`
`A meta—analysis of published reports that assessed
`anal sphincter integrity after vaginal delivery and
`correlated this with continence stated that 77%—83%
`
`(depending on parity) of anal incontinence in par-
`ous women was due to sphincter disruption [B44].
`
`But why doesn't Caesarean section prevent anal
`incontinence, especially when associating perineal
`trauma with loss of bowel control is notjust intuitive,
`but sometimes visibly obvious? Certain aspects of
`vaginal delivery are clearly causally related to anal
`
`73
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0061
`
`

`
`forceps. and
`laceration.
`incontinence: significant
`some episiotomies [855—856]. However this review
`demonstrates that other factors need to be ex-
`
`plored. So one must look to pregnancy and not just
`labour and delivery as an initiating factor. Further
`evidence in favour of this comes from the sphinc-
`ter repair literature cited above. The rapid decay in
`function suggests that another defect is present be-
`sides a gap in the sphincter that remains after the
`early effects of sphincter repair wear off. What this
`is, is not yet known. doesn’t make sense although
`trauma at the pelvic inlet during pregnancy or in ear-
`ly labour [857] seems likely. Sphincter dysfunction
`has been demonstrated in women who have had
`
`Caesarean section [858]. Further indirect evidence
`for the possibility that injury higher in the pelvis may
`be related to Al in pregnant women can be found in
`the association between hysterectomy and Al, an
`association seen more prominently with abdomi-
`nal hysterectomy (TAH) than vaginal hysterectomy
`(VH), and for flatus only [859] (Odds Ratio of TAH
`vs. VH for faeces: 1.2, 0.3-4.7. Odds Ratio for gas:
`18.9. 1.1—327). Pelvic nerve injury during surgery is
`the postulated reason for this difference.
`
`5. NURSING HOME RESIDENCE
`
`The most prominent association with Al by far is
`nursing home residence. Whereas the prevalence
`of Al is probably around 2% to 5% for community-
`dwelling persons, and may rise with increasing age
`to greater than 10%, among nursing home resi-
`dents the prevalence approaches 50% [832-834].
`This is partly explained by Fl being one of the most
`common reasons for nursing home admission.
`In
`a large survey of 18,000 Wisconsin nursing home
`residents. risk factors for faecal incontinence (Fl)
`
`were directly observed by nursing home person-
`nel [833]. Urinary incontinence (Ul) was the great-
`est association with Fl
`(OR = 12.6, 11.5-13.7),
`followed by the loss of ability to perform daily liv-
`ing activities (6.0. 4.7-?.7). tube feeding (?.6. 5.6-
`10.4). physical restraints (3.2. 4.7-7.7), diarrhoea
`(3.3, 2.7-4.2). dementia (1.5, 1.4-1.7), impaired vi-
`sion (1.5. 1.4-1.7), constipation (1.4, 1.3- 1.6). fae-
`cal impaction (1.5, 1.1-2.1). stroke (1.3. 1.2- 1.5)
`male gender (1.2, 1.1-1.3), age and body mass
`index. Inverse associations were noted with heart
`
`disease, arthritis and depression.
`
`6. DIARRHOEA
`
`The importance of diarrhoea of liquid stool in Fl
`cannot be overemphasised [842]. One case se-
`ries noted that 51% of individuals with chronic di-
`
`In the Wisconsin
`arrhoea were incontinent ["187].
`Family Health Survey ofA| [789]. 10 of the 25 sub-
`jects with Fl lived in Milwaukee when the city expe-
`rienced an outbreak of waterborne disease [860].
`Non-infectious causes of diarrhoea must also be
`
`considered. such as inflammatory bowel disease
`[861] and those initiated by sports activities such
`as running [862—863].
`
`7. SURGERY
`
`Al originating from surgery would seem fairly in-
`significant in the general population, since previ-
`ous anal surgery has not been an apparent risk
`factor in the larger surveys. Several operations
`nonetheless can frequently result in Al. Examples
`are midline internal sphincterotomy,
`lateral
`in-
`ternal sphincterotomy.
`fistulectomy, fistulotomy,
`ileo-anal
`reservoir reconstruction,
`low anterior
`rectal resection,
`total abdominal colectomy. and
`
`Stud or Sub rou
`
`Abramov 2005
`
`Altman 2007
`
`Goldberg 2003
`lvlacArthur2005
`
`MacLennan 2000
`
`Melvi|le2005
`
`Varma 2006
`
`-0.94
`
`0.53
`
`0.039 1.15?
`
`4.2%
`
`0.9%
`
`0.058 0.165
`0.039 0.187
`
`43.5%
`33.9%
`
`-0.25 0.655
`
`-0.139 0.371
`
`-0.041
`
`0.44
`
`2.8%
`
`8.6%
`
`6.1%
`
`Total (95% Cl)
`
`100.0%
`
`Odds Ratio
`
`Odds Ratio
`
`IV, Random, 95% Cl
`
`IV, Random, 95% Cl
`
`0.391014, 1101
`
`1.041011. 10.04]
`
`0.98 [0.79, 1.21]
`
`1.00 10.77, 1.40]
`
`1.04 10.72, 1.50]
`
`0.73 10.22. 2.31]
`
`0.8'1’[0.42. 1.30]
`
`0.90 10.41, 2.21]
`
`Heterogeneity: Tau’ = 0.00; Chi’ = 3.57. df = 0 (P = 0.74); r = 0%
`
`Test for overall effect: 2 = 0.20 (P = 0.84)
`
`0.01
`
`0.1
`
`1
`
`10
`
`100
`
`Vaginal Delivery Cesarean Section
`
`Figure 12. Systematic review of Efficacy of Cesarean Section in Preventing Faecal incontinence: 7 Studies
`fulfilling all quality criteria
`
`74
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0062
`
`
`
`

`
`Stud orSub rou
`
`lo Odds Ratio
`
`SE Wei ht
`
`|\l,Fixed,95%C|
`
`IV, Fixed, 95% Cl
`
`Odds Ratio
`
`Odds Ratio
`
`Abramov 2005
`
`La|2003
`
`MacArlhur1997
`
`MacArthur2001
`
`Total (95% Cl)
`
`-0.934 1.466
`
`1.4% 0.39[0.02,6.95]
`
`0.228 1.011
`
`3.0% 1.26 [0.17, 9.11]
`
`-1.412 1.447
`
`1.5% 0.24[0.01,4.15]
`
`-0.3
`
`0.18
`
`94.1% 0.74]0.52,1.05]
`
`100.0% 0.73 [0.52, 1.03]
`
`Heterogeneity: Chi‘ = 1.05, df = 3 (P = 0.79); I’ = 0%
`
`Test for overall effect: 2 = 1.77 (P = 0.08)
`
` 0.001
`
`0.1
`
`1
`
`10
`
`1000
`
`Vaginal Delivery Cesarean Delivery
`
`Figure 13. Systematic review of Efficacy of Cesarean Section in Preventing Faecal incontinence: Vaginal
`Delivery versus Elective Cesarean Section
`
`Stud or Sub rou
`
`'
`
`SE Wei ht
`
`IV, Fixed, 95% Cl
`
`IV, Fixed, 95% Cl
`
`Abramov 2005
`
`0.068 1.576
`
`0.4% 1.07 [0.05_ 23.50]
`
`Odds Ratio
`
`Odds Ratio
`
`
`
`Guise 2007
`
`Guise 2008
`
`La] 2003
`
`MacArthur 199?
`
`MacArthur 2005
`
`Total (95% Ct)
`
`-0.08
`
`0.25
`
`17.5% 0.92 [0.57, 1.51]
`
`0.18 0.135
`
`60.1% 1.20 [0.92, 1.56]
`
`0.639 1.657
`
`0.4% 1.89 [0.07, 48.75]
`
`-2.004 1.476
`
`0.5% 0.13 [0.01, 2.43]
`
`0.0101 0.228
`
`21.1% 1.01 [0.65. 1.58]
`
`100.0% 1.09 [0.89, 1.34]
`
`Heterogeneity: Chi’ = 3.15. df = 5 (P = 0.68); I’ = 0%
`
`Test for overall effect: 2 = 0.85 (P = 0.39)
`
`0'001Emer0g';nCy1 Elecme
`
`1000
`
`Figure 14. Systematic review of Efficacy of Cesarean Section in Preventing Faecal incontinence: Elective
`vs. Emergency Cesarean Section
`
`
`IV, Fixed, 95% Cl
`Stud orSub rou
`Frite|2007
`0.206 0.172
`23.6% 1.23[0.88, 1.72]
`
`IV, Fixed, 95% CI
`
`Odds Ratio
`
`Odds Ratio
`
`
`
`MacLennan 2000
`
`-1.002
`
`0.51
`
`2.7% 0.37 [0.14, 1.00]
`
`Melville 2005
`
`Varma 2006
`
`Total (95% Cl)
`
`-0.259 0.176
`
`22.6% 0.77 [0.55, 1.09]
`
`-0.226 0.117
`
`51.1% 0.80 [0.63, 1.00]
`
`100.0% 0.86 [0.73, 1.01]
`
`Heterogeneity: Chi’ = 7.90, df = 3 (P = 0.05); I’ = 62%
`
`Test for overall effect: Z = 1.83 (P = 0.07)
`
`
`0.01
`
`0.1
`
`
`100
`
`Al|Deliveries Nulliparous
`
`1
`
`10
`
`Figure 15. Systematic review of Efficacy of Cesarean Section in Preventing Faecal incontinence: Nullipa-
`rous women versus Any Form of Delivery
`
`75
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2062 - 0063
`
`

`
`ureterosigmoidostomy. The risk of lateral internal
`sphincterotomy for anal fissure causing Al was
`previously thought to be insignificant when com-
`pared to midline sphincterotomy, but a recent re-
`appraisal of this operation has shown an Al risk
`may be 8% [864]. The risk of Al after fistulotomy
`has been reported to be as high as 18% to 52%
`[865]. New approaches to fissure and fistula have
`recently been developed specifically to lower this
`risk [865—866]. However incontinence after haem-
`orrhoidectomy has also been reported to be as
`high as 33%, an operation in which no sphincter is
`divided [B67]. This suggests either that division of
`the anoderm, not the sphincter may be affecting
`continence, or that the method of ascertainment
`used in published surveys is not accurate. Mixing
`urine and stool has been found to have a predict-
`able effect on anal sphincter control, as does diar-
`rhoea,
`in patients having uretero-sigmoidostomy
`after urinary bladder resection [823]. Patients with
`rectal cancer form a special group in whom can-
`cer issues often mute the continence disturbance
`
`that may result from rectal resection [868] or ra-
`diotherapy [869}.
`
`8. SPECIFIC NEUROLOGICAL AND OTHER
`DISEASES
`
`Several specific diseases have been anecdot-
`ally associated with Al
`in case series, and mech-
`anisms to explain the associations have been
`investigated [S70]. Examples are diabetes [825].
`stroke [87‘l—872], multiple sclerosis, Parkinson's
`disease. systemic sclerosis, myotonic dystrophy.
`amyloidosis. spinal cord injury, imperforate anus,
`Hirschsprung's disease,
`retarded or
`interrupted
`toilet training, procidentia, and any illness caus-
`ing diarrhoea (HIV, IBD. radiation, infection). Many
`of these conditions directly affect patient mobility
`and ability to perform daily living activities or they
`cause diarrhoea or faecal impaction.
`
`9. CONSTIPATION
`
`Constipation may alternate with diarrhoea in ir-
`ritable bowel syndrome making defaecation cha-
`otic and often very urgent. Just as often retained
`faeces lead to anal seepage that cannot be held.
`In the New Zealand survey [790], the 2 of 3 rule
`for categorising an individual as incontinent ex-
`cluded constipated patients, which was also as-
`sessed in their survey, the positive rate fell from
`13.2% to just over 9%. This further demonstrates
`the frequent co-existence of constipation and Al.
`similar to the frequent coexistence of urinary in-
`continence and Al.
`
`10. COHORTS INITIATED BEFORE CLINICAL
`Al ASSESSED FOR SUBSEQUENT DE-
`VELOPOMENT OF Al
`
`Because of a paucity of clinical trials that specifi-
`cally address risk factors and prevention of Al,
`
`the strongest available data to identify risk come
`from cohorts that collected data on potential risk
`factors prior to the onset of incontinence. Pro-
`spectively collected risk assessments for Fl have
`occurred in three nursing home cohorts. Porell
`combined UI and Fl
`into a single outcome vari-
`able and found many positive associations in a
`cohort of 60,000 nursing home residents in Mas-
`sachusetts [873]. Age, African American race,
`cognitive and ADL impairments, predicted the
`outcome, although specific relative risks for in-
`cidence are not presented. Chassange followed
`234 previously non—Fl residents in France for 10
`months, during which 20% had Fl episodes, but
`only 7.5% developed long lasting Fl [874]. The
`others had acute episodes due to diarrhoea or
`impaction. The factors associated with the de-
`velopment of long lasting Fl were urinary inconti-
`nence (Ul) (2.9. 1.8-4.6). decreased mobility (1.8,
`1.1-3.0), and cognitive defects: either as seen in
`an MM