The Malone antegrade continence enema procedure: the Amsterdam experience

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Amsterdam experienceprevalence of 0.7% to 29.6% with no differences found fecal incontinence, and abdominal pain. Less than 5% tostenosis, anorectal malformations), metabolic and gastroin-Journal of Pediatric Surgery (2011) 46, 16031608 Corresponding author.between Europe, Oceania, and North America [1]. The main 10% of children with constipation have an underlyingorganic cause, such as anatomic malformation (ie, analMethods: A retrospective analysis of 23 patients who underwent the construction of a MACE stoma wasperformed. Preoperative and postoperative data were evaluated. A specific questionnaire was used toassess patient satisfaction.Results: A significant increase was found in defecation frequency (1.0 [range, 0-4] pretreatment vs 5.5[range, 0-28] posttreatment per week; P b .006) and a significant decrease in fecal incontinencefrequency (10 [range, 0-14] pretreatment vs 0 [range, 0-14] posttreatment per week; P b .034).Postoperative complications of the MACE procedure were fecal leakage (43%), wound infection (52%),and stomal stenosis (39%). A total of 86% of the patients were satisfied with the results of the Malonestoma (n = 21).Conclusions: The MACE procedure is an effective treatment in children with intractable defecationdisorders. Postoperative complications are, however, not uncommon. Further refinement of the techniquefocused to reduce the complication rate is necessary to expand the application of this approach. 2011 Elsevier Inc. All rights reserved.Constipation is a common problem in childhood with a symptoms of constipation are infrequent painful defecation,0dKey words:Malone antegradecontinence enema;MACE;Intractable constipation;Fecal incontinenceLisette T. Hoekstra a,, Caroline F. Kuijper a, Roel Bakx a, Hugo A. Heij a,Daniel C. Aronson a, Marc A. BenningabaPediatric Surgical Center of Amsterdam, Emma Children's Hospital / AMC, Academic Medical Center, Amsterdam 1105 AZ,The NetherlandsbDivision of Pediatric Gastroenterology, Emma Children's Hospital / AMC, Academic Medical Center, Amsterdam 1105 AZ,The NetherlandsReceived 19 October 2010; revised 7 April 2011; accepted 7 April 2011AbstractBackground: The Malone antegrade continence enema (MACE) procedure has been previouslydescribed as a safe and effective option for the treatment of children with chronic defecation disorderswhen maximal medical therapy and conventional treatment have failed.Purpose: To evaluate clinical success, complications, and quality of life of children with chronicdefecation disorders with a MACE stoma.The Malone antegrade continence enema procedure: theE-mail address: l.t.hoekstra@amc.uva.nl (L.T. Hoekstra).022-3468/$ see front matter 2011 Elsevier Inc. All rights reserved.oi:10.1016/j.jpedsurg.2011.04.050www.elsevier.com/locate/jpedsurgtestinal causes (ie, hypothyroidism, celiac disease, cysticfibrosis), or intestinal nerve and muscle disorders (ie,and Free University Hospital in Amsterdam, the Netherlands.created, following the concept that the direction of theppendiceal peristalsis was toward the colon. The Ransleychnique for the VQZ skinplasty was applied in the secondart of the series, trying to prevent stomal stenosis [6]. In casee appendix was unavailable, a neo-appendix was createdsing tubularized colon, or a button in either the ascendingolon or in the sigmoid was used. The Malone stoma wasonducted by laparotomy or, in the second half of the seriesy a laparoscopic approach, depending on the experience ofe surgeon. Surgical complications were classified as major,efined as requiring operative reintervention or minor,efined as not requiring operative reintervention..2. Questionnairereminded by telephone. The questionnaire was developed atour center (see Appendix) and evaluated the indication for1604 L.T. Hoekstra et al.Of all patients, data regarding demographics, preoperativecomplaints (defecation frequency, fecal incontinence fre-quency, abdominal pain, use of laxatives and enemas, orrectal washouts), indication for MACE, postoperative effecton defecation and continence, surgical technique, complica-tions and revision surgery, and the use of antibiotics wereevaluated using patient files, operative reports, and officenotes. All patients with intractable constipation were treatedwith high dosages of oral laxatives before operation. Almostall patients used enemas preoperatively and/or requiredcolonic washouts. Colonic washouts were performed,usually in the morning with water 20 mL/kg (bodytemperature), according to the recently published Dutchguideline for children with constipation [5]. The volume wasgradually increased until we found the right volume for theindividual child. A nonvalidated questionnaire was used toassess patient satisfaction.1.1. Surgical techniqueIn the original technique, Malone used a reversedappendix as a conduit [4]. In the present series, the appendixwas neither reversed nor was a primary antireflux valveHirschsprung's disease, spina bifida, visceral myopathies).Acute simple constipation is traditionally treated with ahigh-fiber diet and sufficient fluid intake, and combined withthe request to fill out a bowel diary and toilet training,whereas the treatment of chronic constipation includes 4phases: (1) education, (2) disimpaction, (3) prevention of re-accumulation of feces and 4) follow-up (naspghan guidelines2006). Despite this intensive medical and behavioraltreatment approach, follow-up studies have shown thatafter 5 years, approximately 50% of the children still havecomplaints of constipation [2,3].The Malone antegrade continence enema (MACE) hasfirst been described in 1990 by Malone et al [4] for childrenwith chronic, severe defecation disorders. This surgicalintervention has been suggested as a safe and satisfactorytreatment option when long-lasting oral and rectal treatmentin combination with conservative measures has failed. Todate, insufficient knowledge exists on the quality of life andcomplications in children with a MACE stoma or colonicbutton. Therefore, the aim of this study was to evaluateclinical success, complications, and quality of life of childrenwith chronic defecation disorders treated with a MACEstoma or button.1. Patients and methodsA retrospective analysis was performed in 23 patients (14boys and 9 girls) with intractable constipation and/or fecalincontinence who received a MACE stoma between July2002 and May 2008 in the Emma Children's Hospital/AMCthe MACE procedure, complications, reoperation(s), use ofMACE, social functioning, patient satisfaction, choice forsurgery in retrospect, and the patients' recommendation toother patients. The patients' satisfaction was evaluated on ascale from 1 to 10. In this scale, a higher score represents ahigher level of satisfaction. We reported a number of 6 orhigher as satisfactory.1.3. Statistical analysisStatistical analysis was performed using SPSS software(Statistical Package of the Social Sciences 14.0 forWindows; SPSS, Chicago, Ill). Demographic characteristicswere compared using the paired Student's t test forcontinuous outcomes. A P value of less than .05 wasconsidered statistically significant.2. ResultsA MACE procedure was performed in 23 children withsevere defecation disorders, not manageable with conserva-Table 1 Baseline characteristicsBefore MACESex (n)Male 14Female 9Median age at surgery (y) 7.3 (2-17)Symptom duration (y) 4.7 (1-11)Defecation frequency/wk 1.0 (0-4)Fecal incontinence/wk 10 (0-140)Abdominal pain (%) 57Results are median (range).Participating patients received a nonvalidated question-naire by mail to determine the effect of the surgicalprocedure. In case of no response, the patient was kindlyatepthuccbthdd1lasted longer (105 minutes compared to 42-80 minutes). Anincrease in the median operation time was seen hereafter,when the use of the VQZ-plasty was introduced. Between2007 and 2008, the operations lasted an average of 130minutes (SD, 19.87 minutes). Most of them were performedusing the laparoscope.After surgical intervention, the (median) defecationfrequency for all children with constipation increased from1.0 (range, 0-4) to 5.5 (range, 0-28) per week (P b .006).A significant decrease in the (median) fecal incontinencefrequency from 10 (range, 0-140) to 0 (range, 0-14) perweek was found (P b .034). In the group of children withconstipation without fecal incontinence (n = 4), themedian defecation frequency increased from 1.0 (range,0-3) to 3.0 (range, 0-5) per week (P b 1.00) after surgery.Children initially presenting complaints of constipationTable 2 ComplicationsMinor complications n Major complications nStomal stenosis 6 Stomal stenosis,persistent complaints1Prolaps 5 Stenosis, anastomticleakage, abcesses1Fecal leakage 10 Stenosis, wound infection 1Pain 7 Fistula 1Wound infection 11Catheter problems 7Persistent constipation 3Stomal bleeding 2Surgical complications were classified as major, defined as requiringoperative reintervention, or minor, defined as not requiring operativereintervention.1605MACE proceduretive means. The demographics and complaints are shown inTable 1. The underlying diagnosis was idiopathic constipa-tion with and without fecal incontinence in 15 children, ofwhich 11 constipated patients were fecally incontinent and 4constipated patients without fecal incontinence. Otherunderlying diseases were spina bifida in 5 children andHirschsprung's disease in 3 children. In the children withspina bifida, 40% presented with constipation and fecalincontinence, whereas the remaining patients had constipa-tion as the only symptom. One of the children withHirschsprung's disease had complaints of constipation andfecal incontinence; the other 2 presented with severeconstipation only.Thirteen of these patients underwent a MACE operationusing the appendix. In 4 other patients, a Malone stomawas constructed by tubularized colon (neo-appendix)because of the absence of the native appendix. In 5patients, a button was placed in the ascending colon, and in1 patient a button was placed in the sigmoid. Until 2004,the Malone procedure was conducted by laparotomy andthe operation time required more than 71 minutes ataverage (SD, 21.47 minutes). Only one procedure wasperformed laparoscopically assisted in that period andTable 3 Complications separated for surgical approachComplications (total no. of patients; %) Appendicostomy (n [%])Wound infection (12; 52%) 6 (50)Stomal stenosis (9; 39%) 5 (56)Catheter problems (7; 30%) 4 (57)Prolaps (5; 22%) 4 (80)Pain (7; 30%) 4 (57)Constipation (4; 17%) 4 (100)Stomal bleeding (1; 4%) 0 (0)Hernia cicatricalis (1; 4%) 0 (0)Eczema (1; 4%) 0 (0)Abcesses (1; 4%) 0 (0)and fecal incontinence showed a significant increase in(median) defecation frequency from 0.5 (range, 0-4) to 7.0(range, 0-28) per week (P b .048) and a decrease inmedian fecal incontinence frequency from 21.0 (range, 4-70) to 0 (range, 0-14) per week (P b .068). Postopera-tively, 48% of patients still suffered periodically fromabdominal pain.The median length of hospital stay was 8 days (range,6-60). The median duration of follow-up was 4.00 2.29(range, 1-7) years. All 23 patients in our series had eitherminor or major postoperative complications (Table 2).Overall, the most commonly reported complications werewound infection (n = 12; 52%) and fecal leakage (n =10; 43%). Stomal stenosis developed in 9 patients (39%).Table 3 depicts the complications for the differentsurgical approaches. Most complications were seen inchildren who underwent an appendicostomy. In 3patients, the VY technique was used between 2002 and2004; 2 of these 3 patients developed stomal stenosis.After the introduction of the VQZ technique, 22complications were observed in 9 patients, but lessstomal stenosis (33%) occurred.Catheter problems and enema leakage were the mostcommon complications observed in patients who underwentthe VQZ technique. In total, 4 patients (17%) neededNeo-appendicostomy (n [%]) Button cecostomy (n [%])3 (25) 3 (25)3 (33) 1 (11)1 (14) 2 (29)0 (0) 1 (20)1 (14) 2 (29)0 (0) 0 (0)1 (100) 0 (0)1 (100) 0 (0)1 (100) 0 (0)1 (100) 0 (0)Table 4 (In)continence after surgery1606 L.T. Hoekstra et al.reoperation related directly to postoperative complications.In one patient, a new Malone stoma had been performedbecause of stomal stenosis and persistent complaints ofconstipation and fecal leakage. One child was reoperatedbecause of stomal stenosis, anastomotic leakage, andintraabdominal abscesses. A wound infection together witha stomal stenosis after a percutaneous button placement wasseen in another patient. Eventually, a laparoscopic appendi-costomy has been performed in this patient. Another patienthad to be reoperated because of a fistula. Fourteen patients(61%) had to be readmitted because of complicationsassociated with the stoma.According to the Malone criteria, full success (totallyclean or experiencing only minor leakage on the night of thewashout) was achieved in 20 patients, partial success (cleanbut having significant rectal leakage, occasional major leak,and/or still wearing protection) in 2 patients, and failure in 1patient (regular fecal incontinence episodes or constipationpersisted) [7]. Table 4 depicts fecal (in)continence after thedifferent surgical procedures.2.1. AntibioticsUntil 2006, 10 patients were given intravenous antibioticsfor 24 hours after the surgical intervention. In the sameperiod, 2 patients received antibiotics for 3 consecutive days.From 2007 onward, antibiotics were routinely administeredfor 5 days (11 patients). In the first period, 6 woundinfections occurred in 14 patients. In the second period(2007-2008), 6 wound infections occurred in 9 patients(differences not significant).2.2. Quality of life (QoL)A total of 22 questionnaires were returned (response rate96%). Before construction of the Malone stoma, 50% of thepatients reported that both oral and rectal therapy had notbeen effective. In 46% of the children, rectal enemas,although effective, were no longer tolerated. Analysis of thedata showed that 86% of the patients were satisfied with theresults of the Malone stoma, with a median score of 8 (range,6-10). No restrictions in daily life after the surgical procedureTotal no of patients; % Appendicostomy (n [%])Fecal continent (13; 57%) 8 (62)Fecal incontinent (10; 43%) 5 (50)were seen in 60% of patients. A minority of the patientsexperienced some restrictions at school and with sports. Themajority of children experienced the daily washouts as timeconsuming. A total of 73% of these patients wouldrecommend this procedure to other patients with intractabledefecation disorders.3. DiscussionThis study clearly shows that the MACE procedure is aneffective alternative treatment option in children withintractable constipation and/or fecal incontinence notresponding to conventional conservative oral and rectallaxative therapy. Our data show a significant increase indefecation frequency and a significant decrease in fecalincontinence after the MACE procedure. Despite the highnumber of patients experiencing minor complications of thissurgical intervention, such as wound infection and fecalleakage or stomal stenosis that did not require surgicalintervention, most of the patients were satisfied andrecommended the MACE procedure to other patients.Annually, more than 350 new patients with functionalconstipation are referred to our specialized tertiary pediatricbowel clinic. In recent years, we reported a 60% success rateafter 1 year of intensive treatment using a combination oforal laxatives and behavioral therapy [7]. Most of the patientswere treated successfully within 5 years of therapy. Of all ourpatients with functional defecation disorders, only 1%required a MACE procedure. These children were treatedfor longer periods with high dosages of oral laxatives, orallavage, or intensive rectal washouts, indicating that only rarecases depend on surgery, unless we are too restrictive withour indication for surgical therapy. Children included in thisstudy represent a highly selected group of children withsevere constipation, treated for a long period in a tertiary veryspecialized motility center. These patients were hospitalizedseveral times, failed multiple intensive medical oral andrectal regimens, or refused either oral medications orretrograde enemas.The MACE procedure has been previously described asa safe and effective treatment option for children withintractable defecation disorders such as functional consti-pation and slow transit constipation [8,9]. A recentlypublished systematic review evaluated 24 studies, including676 patients, which reported the experience of the ACEprocedure. Overall continence was achieved in 93% of thepatients [10]. In accordance with these studies, our studyshows a similar success rate of 86%. Despite the highsuccess rates of the Malone procedure, complications areNeo-appendicostomy (n [%]) Button cecostomy (n [%])2 (15) 3 (23)2 (20) 3 (30)often described. The most commonly reported complicationaffecting clinical outcome has been stomal stenosis, beingreported in up to 30% to 50% of patients [9,11,12].Furthermore, fecal leakage, pain or difficulty with stomalcatheterization, stoma granuloma, and intraabdominaladhesive obstruction were described. Some of thesecomplications required an operative reintervention. In our improved after the surgical intervention [19]. In children withorganic or functional constipation and/or fecal incontinence1607MACE procedureseries, wound infection, fecal leakage, and stoma stenosisoccurred in approximately 50% of the patients. No data areavailable concerning the use of prophylactic antibiotics toprevent postoperative wound infections. In our series, eventherapeutic use of antibiotics (during 5 days postoperative-ly) did not decrease the rate of wound infections. Therelatively high leakage rate may very well be dependent onthe fewer appendiceal plications we performed primarily. Itprobably shows that the theoretical mechanism of peristalsisgoing from the tip of the appendix toward the coecum isless protective against leak than expected. This aspectclearly needs technical refinement, that is, cecal plicationsin all Malone stomas, as also the introduction of the VQZ-plasty diminished the amount of stomal stenosis.No differences in number and nature of complications overa specific period were seen after changing to the laparoscopi-cally assisted MACE. Although the median operation timeincreased when the MACE procedure was performed lapar-oscopically assisted, no conclusions can be drawn because itwas confounded with the introduction of the VQZ-plasty.Other studies showed better [13] or comparable [14]operative times and less complications in patients undergoinga laparoscopic ACE procedure. Lynch et al [15] reviewed theresults of laparoscopic and open antegrade continence enemaprocedures. Improvement of fecal incontinence was achievedin 90% of patients treated by the laparoscopic variant ofMACE compared with 61% to 78% in patients whounderwent an open procedure [12]. The incidence of stomalleakage was 6.7% in the laparascopic group and between 5.6and 15% in the open appendicostomy group. A more recentstudy reported comparable rates of stomal leakage andstenosis after open and laparoscopic ACE [16].A systematic review has taken into account the recentimprovements in the techniques and outcomes of the MACEprocedure [10]. Advancements in techniques, better-trainedstoma care nurses, and better stoma appliances areresponsible for better outcomes in the last 5 years. Sinha etal [10] showed that various other methods are described inthe literature, such as tubularized colon, tubularized ileum,left-sided percutaneous endoscopic colostomy, cecal button,cecostomy tube, laparoscopic-assisted cecal button, andlaparoscopic-assisted percutaneous colostomy. The trend istoward minimally invasive procedures, mainly laparoscopic-assisted approaches, which are also more frequently appliedin our center. The experiences with the antegrade colonicenema stopper are described to prevent and treat stoma-related complications [17]. The ACE stopper did preventstomal stenosis; however, a long-term follow-up is needed toestablish the true effectiveness.Despite the high complication rate in our series, mostpatients and parents (86%) were satisfied with the results thatwere achieved by the construction of the Malone stoma.Similar satisfaction rates were reported by others [18,19], alsousing nonvalidated questionnaires. More importantly, one ofthese studies showed that social confidence was significantlynot responding to conventional conservative laxativetherapy. Although a significant improvement was observedin all defecation-related parameters, morbidity was high,with a high incidence of postoperative complications such aswound infection, fecal leakage, and stomal stenosis. Despitethese postoperative complications, most of the patients weresatisfied and would recommend the MACE procedure toother patients. Prospective studies, using standardized bowelquestionnaires, validated QoL scores, strict success criteria,and a long term follow-up, are necessary to determine theefficacy of this invasive surgical procedure. To minimizecomplications and to anticipate and treat complications,technical refinements like cecal plication over the basis of theappendix are necessary, and these procedures probably mayhave to be performed by at least 2 experienced pediatricsurgeons in centers with specific expertise on the aftercareand follow-up of these patients.Appendix A.1.) What was the indication for the Malone stoma?- Laxatives were ineffective- Rectal wash-outs were unsuccessful- Rectal wash-outs were psychosocially unacceptable- Other:2.) Did complications occur?- No complications- Wound infection- Stomal stenosis- Catheter problems- Enema leakage- Prolapse- Pain- Persistent constipation- Stomal blood lossfrequent episodes of constipation and fecal incontinence, lowerlevels of quality of life were reported regarding disease-specific emotional and social functioning [7]. Children with areconstructed anorectal malformation reported lower quality oflife scores than controls. Therefore, it is of utmost importancethat attention should be paid to the rehabilitation of fecalcontinence after surgery [20]. A study by Hartman et al [21]showed no differences in quality of life domains in childrenand adolescents with anorectal malformations or Hirsch-sprung's disease compared with a reference group, althoughsome patients reported lower levels of defecation-relatedglobal disease-specific functioning and psychosocial compe-tencies. Quality of life improved over time in this patientgroup. To maintain an optimal level of quality of life, it isimportant to direct treatment both to reducing symptoms and toenhancing psychosocial competencies [22].In conclusion, the MACE procedure is an effectivealternative treatment option in children with intractable3.) Are you reoperated or re-admitted? If yes, where?4.) Do you still use the Malone stoma? If not, why?5.) Is the Malone stoma closed?6.) How are you doing currently?- Clean- Incontinent- Stomal stenosis- Enema leakage- Pain- Malone stoma is removed- Persistent constipation- Other:7.) Do you experience restrictions in daily life? If yes,what kind of restrictions?8.) Are you satisfied with the Malone stoma? Can youindicate this on a scale from 1 to 10 with 1 = notsatisfied till 10 = very satisfied.561-4.[3] Voskuijl WP, Reitsma JB, van GR, et al. Longitudinal follow-up of[6] Landau EH, Gofrit ON, Cipele H, et al. Superiority of the VQZ overthe tubularized skin flap and the umbilicus for continent abdominalstoma in children. J Urol 2008;180:1761-5.[7] Curry JI, Osborne A, Malone PS. How to achieve a successful Maloneantegrade continence enema. J Pediatr Surg 1998;33:138-41.[8] Bongers ME, van DM, Benninga MA, et al. Health related qualityof life in children with constipation-associated fecal incontinence.J Pediatr 2009;154:749-53.[9] Marshall J, Hutson JM, Anticich N, et al. Antegrade continenceenemas in the treatment of slow-transit constipation. J Pediatr Surg2001;36:1227-30.[10] Sinha CK, Grewal A, Ward HC. Antegrade continence enema (ACE):current practice. Pediatr Surg Int 2008;24:685-8.[11] Curry JI, Osborne A, Malone PS. The MACE procedure: experience inthe United Kingdom. J Pediatr Surg 1999;34:338-40.[12] Wilcox DT, Kiely EM. The Malone (antegrade colonic enema)procedure: early experience. J Pediatr Surg 1998;33:204-6.[13] Nanigian DK, Kurzrock EA. Intermediate-term outcome of thesimplified laparoscopic antegrade continence enema procedure: lessis better. J Urol 2008;179:299-303.[14] Hedican SP, Schulam PG, Docimo SG. Laparoscopic assisted1608 L.T. Hoekstra et al.children with functional nonretentive fecal incontinence. Clin Gastro-enterol Hepatol 2006;4:67-72.[4] Malone PS, Ransley PG, Kiely EM. Preliminary report: the antegradecontinence enema. Lancet 1990;336:1217-8.[5] Tabbers MM, Boluyt N, Berger MY, et al. Richtlijn Obstipatie bijkinderen van 0 tot 18 jaar. NVK 2009.10.) Would you choose again for the Malone stoma if it wasa possibility?11.) Will you recommend this procedure to other childrenwith the same complaints?12.) Do you have any remarks or suggestions?References[1] van den Berg MM, Benninga MA, Di LC. Epidemiology of childhoodconstipation: a systematic review. Am J Gastroenterol 2006;101:2401-9.[2] Staiano A, Andreotti MR, Greco L, et al. Long-term follow-up ofchildren with chronic idiopathic constipation. Dig Dis Sci 1994;39:reconstructive surgery. J Urol 1999;161:267-70.[15] Lynch AC, Beasley SW, Robertson RW, et al. Comparison of resultsof laparoscopic and open antegrade continence enema procedures.Pediatr Surg Int 1999;15:343-6.[16] Karpman E, Das S, Kurzrock EA. Laparoscopic antegrade continenceenema (Malone) procedure: description and illustration of technique.J Endourol 2002;16:325-8.[17] Lopez PJ, Ashrafian H, Clarke SA, et al. Early experience with theantegrade colonic enema stopper to reduce stomal stenosis. J PediatrSurg 2007;42:522-4.[18] Schell SR, Toogood GJ, Dudley NE. Control of fecal incontinence:continued success with the Malone procedure. Surgery 1997;122:626-31.[19] Yerkes EB, Cain MP, King S, et al. The Malone antegrade continenceenema procedure: quality of life and family perspective. J Urol2003;169:320-3.[20] Bai Y, Yuan Z, Wang W, et al. Quality of life for children withfecal incontinence after surgically corrected anorectal malformation.J Pediatr Surg 2000;35:462-4.[21] Hartman EE, Oort FJ, Sprangers MA, et al. Factors affecting quality oflife of children and adolescents with anorectal malformations orHirschsprung disease. J Pediatr Gastroenterol Nutr 2008;47:463-71.[22] Hartman EE, Oort FJ, Aronson DC, et al. Explaining change in qualityof life of children and adolescents with anorectal malformations orHirschsprung disease. Pediatrics 2007;119:e374-83.9.) What is your experience with the Malone stoma?The Malone antegrade continence enema procedure: the Amsterdam experience1. Patients and methods1.1. Surgical technique1.2. Questionnaire1.3. Statistical analysis2. Results2.1. Antibiotics2.2. Quality of life (QoL)3. DiscussionAppendix A.References

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