Review

Eur Surg https://doi.org/10.1007/s10353-021-00703-1

Appendectomy and women’s reproductive outcomes: a review of the literature

Lucia Merlino · Alessandra Chiné · Giulia Carletti · Federica Del Prete · Massimo Codacci Pisanelli · Luca Titi · Maria Grazia Piccioni

Received: 2 February 2021 / Accepted: 12 March 2021 © The Author(s) 2021

Summary Methods The search was conducted in PubMed and Background The most frequent abdominal there was no limitation set on the date of publication. performed for benign disease in females of fertile age All studies regarding populations of female patients is appendectomy, which remains among the most who had undergone appendectomy for inflamed ap- common and is a possible cause of peri- pendix, perforated appendix, or negative appendix be- toneal adhesions. The fact that appendectomy can tween childhood and the end of the reproductive pe- cause adhesions may lead one to think that this may riod were included. be a relevant risk factor for infertility; however, there Results Some authors believe that pelvic surgery can is no universal agreement regarding the association cause adhesions which can potentially lead to tubal between appendectomy and fertility. The aim of this infertility by causing tubal obstruction or by altering review is to evaluate weather appendectomy may motility of fimbriae, tubal fluid secretion, and embryo have a relevant impact on female fertility. transport. On the other hand, the most recent evi- dence reported that removal of the appendix seems to be associated with an increased pregnancy rate in large population studies. L. Merlino · A. Chiné · G. Carletti · F. Del Prete · Conclusion Despite the existence of contrasting opin-  M. G. Piccioni ( ) ions concerning fertility after appendectomy, the most Department of Maternal and Child Health and Urological Sciences, Policlinico Umberto I, “Sapienza” University of recent evidence suggests that appendectomy may ac- Rome, Viale del Policlinico 155, 00161 Rome, Italy tually lead to improved fertility and decreased time [email protected] to pregnancy. Appendectomy seems to be correlated with improved fertility and higher pregnancy rates. L. Merlino [email protected] Keywords Infertility · Complicated appendicitis · A. Chiné Abdominal surgery · Abdominal adhesions and [email protected] reproduction · Tubal occlusion G. Carletti [email protected] Introduction F.Del Prete [email protected] The World Health Organization defines infertility as the failure to conceive after more than 1 year of un- M. Codacci Pisanelli protected sexual intercourse. It has been estimated Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy that 50 to 80 million women worldwide are diagnosed [email protected] with infertility every year [1]. Some of the most common causes of infertility are L. Titi reproductive system diseases (endometriosis, uterine Department of , Section Obstetrical Care, “Sapienza” University of Rome, Policlinico Umberto I, Rome, leiomyomas, previous urinary tract infections, and Italy surgeries or other invasive procedures), endocrine [email protected] imbalances, advanced age at conception, drugs and

K Appendectomy and women’s reproductive outcomes Review

alcohol abuse, altered immune responses, stress, and appendectomy, appendectomy complications, and chronic diseases [2]. Currently, the most common reproductive outcomes. Cohort studies, case–control cause of infertility in women is probably fallopian studies, meta-analysis, reviews, and systematic re- tube dysfunction and in particular a compromised views were analyzed. All studies regarding popula- tubal patency [3]. Tubal occlusions and pelvic adhe- tions of female patients who had undergone appen- sions are major causes of infertility and have been es- dectomy for inflamed appendix, perforated appendix, timated to account for approximately 35% of infertility or negative appendix between childhood and the end in couples and for more than 50% of female infertil- of the reproductive period were included in the cur- ity [4, 5]. According to recent literature, up to 5% of rent review. Excluded were benign abdominal surgery infertility cases can be ascribed to iatrogenic interven- for causes other than appendectomy and non-English tions which are thought to interfere with fertility by studies. favoring the formation of intraabdominal adhesions, thereby leading to fallopian tube dysfunction [6]. Ad- Results hesions are known to be the consequence of tissue trauma during surgery and it would appear that scar In our literature search we have found contrasting tissue formation may result in infertility by distorting opinions regarding the impact of appendectomy on adnexal anatomy, thus interfering with embryo trans- fertility. port [7]. Despite a recent decline in the frequency of In the past, several studies suggested an associ- appendectomy due to the increasingly popular con- ation between complicated appendicitis and female servative approach and improved diagnostic workup infertility [18, 21, 26, 28, 29]. Thompson et al. and [8–10], appendectomy remains the most frequent Mueller et al. found that appendiceal perforation benign abdominal surgery performed in females of increased the risk of primary tubal infertility and of fertile age and consequently remains a major cause secondary tubal infertility [18, 33]. It was also stated of intraabdominal adhesions [11]. Possible causes of in several old textbooks that perforated appendicitis adhesions in this setting are the acute inflammatory in childhood is associated with an increased risk of response of appendicitis itself, the trauma of surgery, tubal infertility [30, 31]. Brikeenfield et al. in 1982 and postoperative inflammation due to a foreign body and Lalos et al. in 1988 found an increased appen- reaction [11, 12]. dectomy rate of 20% and 29%, respectively, in women The evidence that appendectomy can cause forma- seeking care at a fertility clinic compared to 7–10% in tion of pelvic adhesions may lead one to think that this the general population [14, 32]. In a review about the could be an important risk factor for infertility. In the risk factors for tubal infertility, Lalos et al. found that literature there is controversy about this correlation out of 120 women with diagnosed tubal dysfunctions, and some studies have found no evidence for tubal 59% had a positive history for pelvic surgery and 42% infertility after appendectomy [13–15]. Other studies had history of pelvic inflammation. Based on these have rather found that appendectomy with or with- assumptions it was suggested that previous pelvic out pathologically confirmed appendicitis could be surgery and inflammation could be relevant factors indirectly associated with an increased rate of infer- for development of tubal infertility [14]. More recently tility by virtue of an increase in the rate of ectopic in 2019, Becker et al. also noticed a correlation be- pregnancies [16, 17]. Complicated appendicitis asso- tween appendectomy and infertility. They reported ciated with perforation, peritonitis, or pelvic abscess that almost 25% of women seeking care at their fer- has been associated by some authors with normal fer- tility clinic had a positive history of appendectomy, tility [18–24], and by others with substantially reduced suggesting a possible association. However, after fur- fertility [25–29]. Similarly, appendectomy, regardless ther investigation, Becker et al. did not find impaired of the severity of appendicitis and even in case of tubal patency on chromopertubation. Based on this, negative appendicitis, has been associated by some the authors hypothesized that the observed increased authors with normal fertility [12, 14, 15]andbyothers rate of infertility after appendectomy may possibly with significantly reduced fertility [16, 17]. be linked to factors other than tubal patency such as The aim of this review is to bring attention to this fibrosis in and around the ovarian capsule, decreased controversial topic and to evaluate weather benign ab- ciliary movements and secretion of tubal fluid, or dominal surgery and appendectomy in particular may alterations in movements of the fimbriae which could have an impact on female fertility. have been compromised by local inflammation after appendicitis [33]. Bellati et al. in 2014, in a study Materials and methods about female fertility after unilateral ovariectomy, found a lower birth rate in patients with a history The search was conducted in the PubMed database of appendectomy and stated that despite not being and shall be deemed updated as of December 2020. statistically significant, it was not possible to exclude There was no limitation set on the date of publica- that this difference could be ascribed to development tion. The keywords used for the PubMed search were of tubal infertility following appendicitis [6]. appendicitis, complicated appendicitis, infertility,

Appendectomy and women’s reproductive outcomes K Review

ous clinical experiments. -based ma- terials reduced adhesions after intestinal and gyne- cological surgery [33, 38, 43]. Mechanical barriers are considered effective in surgery for subfertility. In some clinical studies, adjuvants such as dexametha- sone, Ringer’s lactate, and dextran have never been proved to be effective [40, 44]. In a recent review by Canis et al., several devices for prevention of adhe- sions were compared: GoreTex (W.L. Gore & Asso- ciates, Inc, Newark, DE, USA), Interceed (Johnson & Johnson, New Brunswick, NJ, USA), Seprafilm (Baxter, Deerfield, IL, USA), Icodextrin, Hyalobarrier (Nordic Fig. 1 Laparoscopic appendectomy Pharma, Ismaning, Deutschland). Although no study has shown superiority of one product over another, Other than the long-term effects of appendicitis some studies have noticed a decrease in the adhe- and or appendectomy, there are a few case reports sions observed in the treated groups at second-look in the literature on some acute post-appendectomy [45]. Despite the results not being statis- complications likely to have an impact on fertility. tically significant, considering the fact that no adverse Singh-Ranger et al. in 2008 reported the case of a 17- effects were reported, the use of these devices could year-old girl who developed acute coliform salpingitis be suggested. 3 months after appendectomy [34]. Nyogi et al. in On the other hand, no evidence was found regard- 2009 and Limberg et al. in 2015 described two similar ing the efficacy of surgical barriers, or antiinflamma- cases of recurrent hydrosalpinx ensuing after surgery tory agents in reducing the risk of postsurgical adhe- for perforated appendicitis [35, 36]. Vyas et al. in sions [7]. 2008 presented a case of tubal/ovarian abscess due to The abovementioned findings would apparently an appendicolith that appeared to have migrated into further support the hypothesis that appendicitis or, the right fallopian tube [37]. more specifically, perforated appendicitis could be In the literature there are contrasting opinions re- directly linked to tubal and therefore tubal garding the incidence of postsurgical adhesions in la- infertility. paroscopic and open appendectomy (Fig. 1). Some However, several authors have published evidence authors believe that the risk of developing anterior that appears to be in strong contrast to these findings. abdominal wall adhesions is likely to be lower after When looking into the most recent literature, very in- laparoscopy than after laparotomy because the risk teresting data have emerged which seem to suggest seems to be correlated to the length of the abdom- the exact opposite of what was once believed to be inal incisions [13]. Moreover, postoperative surgical the effect of appendectomy on fertility. In fact, ac- scar infection, another factor known to favor adhe- cording to several recent articles, it would appear that sion, is significantly lower after laparoscopy than after appendectomy could actually increase fertility. laparotomy [7]. Lundorff et al. observed fewer adhe- In 1977, Geerdsen reported that perforated appen- sions after laparoscopic tubal surgery than after open dicitis in girls showed no correlations with infertility. surgery [38]. De Wilde et al. performed a second- Itwouldinfactappearthattheinflammatoryprocess look laparoscopy 3 months after either open or la- caused by perforated appendicitis resolves completely paroscopic surgery for acute appendicitis and found with appendectomy and adequate antibiotic treat- that 80% of the patients who underwent open appen- ment [26]. Also, Puri et al. reported that perforated dectomy had abdominal adhesions, whereas after la- appendicitis in prepubertalchildrenhasnoimpacton paroscopic appendectomy adhesions were found in the development of tubal infertility. With improved only 20% of patients [39]. Vrijland et al. came to diagnostic tests, earlier surgery, and the use of an- the same conclusion, stating that laparoscopic surgery tibiotics directed against anaerobes like Bacteroides appears to induce fewer adhesions than open surgery spp., the incidence of intraabdominal abscess after [40]. In contrast, other authors have found that the perforated appendicitis is significantly diminished benefit of a laparoscopic approach in terms of adhe- and this is likely to further minimize any risk of tubal sion prevention is not as certain as suggested by the damage arising from perforated appendix ([20, 46]; previous clinical impression and by the results of early Fig. 2). Mueller et al. have estimated that the pro- laparoscopic adhesiolysis. In fact, with the exception portion of tubal infertility attributable to appendiceal of tubal sterilization, procedures performed by laparo- perforation is 0.9% [29]. tomy and laparoscopy were followed by identical rates Urbach et al., considering the low prevalence of ap- of readmissions due to postoperative adhesion com- pendix perforation and the low level of evidence corre- plications [41, 42]. lating infertility to appendiceal perforation, consider The role of adjuvants in preventing postoperative it unlikely that appendix perforation has a relevant im- adhesion formation has been demonstrated in vari- pact on the burden of infertility at a population level.

K Appendectomy and women’s reproductive outcomes Review

Fig. 2 Acute suppurative appendicitis showing diffuse mu- Fig. 3 Gangrenous appendicitis with necrosis of the wall of cosal ulceration and transmural acute infammation with ex- the appendix (H&E stain) tension into the periappendiceal fat (H&E stain)

They reported that women with a positive history of ploration and appendectomy might have been caused perforated appendicitis had comparable rates of first by ovulation-related pain leading to negative appen- birth and parity to the control women [24]. These find- dectomy and at the same time acting as a surrogate ings are in line with data reported in a recent meta- marker of increased fertility [11]. In a recent system- analysis by Elraiyah et al., which showed that appen- atic review about the long-term complications of ap- dectomy is not associated with infertility but is instead pendectomy published in 2018, five cohort studies re- significantly associated with an increased risk of ec- porting on fertility were included [11, 23, 26, 48]. Four topic pregnancy [47]. of these studies had similar outcomes, suggesting that In addition to demonstrating that appendectomy patients with a positive history of appendectomy had did not affect female fertility, in recent years, vari- an increased pregnancy rate when compared to con- ous authors have reported that the execution of this trol groups. Three of the studies included in the review surgery could improve the female pregnancy rate. In assessed the adjusted HR for first pregnancy, show- an epidemiological study published in 1999, Anders- ing increased pregnancy rates for the appendectomy sonetal.werethefirsttoreportthatwomenwho groups with HRs of 1.20 (95% CI: 1.10–1.31), 1.34(95% had negative appendectomy showed an increased first CI: 1.32–1.35), and 1.54 (95% CI: 1.52–1.56), respec- birth rate and had their first child at an earlier age on tively [49]. average, reaching a higher parity than control women. However, none of these studies included informa- They showed an increased pregnancy rate after ap- tion about perforated and non-perforated appendici- pendectomy for non-perforated appendicitis with an tis. Some authors suggested that since the majority HR (hazard ratio) of 1.11 (95% CI: 1.07–1.15) as well as of acute appendicitis cases occur in the luteal phase after removal of a normal appendix with an HR of 1.48 of the menstrual cycle, the fluctuations of female sex (95% CI: 1.42–1.54). Perforated appendicitis did not hormones might play a direct role in the development show any significant change in pregnancy rate with an of the inflammatory process in the appendix [50, 51]. HR of 0.95 (95% CI: 0.88–1.04) [23]. More recent stud- Thus, female sex hormone fluctuations may influ- ies on this topic such as those of Li Wei et al. would ap- ence the initial inflammatory process in the lymphoid pear to corroborate the theory according to which ap- tissue of the appendix, which subsequently becomes pendectomy could improve female fertility and sub- engorged and obstructs the lumen, leading to acute sequently lead to higher pregnancy rates [11, 48]. In appendicitis [52]. Wei et al. gave other possible expla- a cohort study on this topic, Wei et al. reported a sta- nations for this phenomenon in a second larger cohort tistically significant increase in pregnancy rate after study. In this cohort study it was reported that not appendectomy and early appendicitis. More specifi- only appendectomy but also tonsillectomy seemed to cally, in the appendectomy cohort, the subgroup with be correlated with an increased pregnancy rate and complicated purulent or gangrenous appendicitis had decreased time to pregnancy. This study included lower pregnancy rates when compared with the group a total of 54,675 appendectomy patients, 112,607 ton- who had negative appendicectomy but similar preg- sillectomy patients, and 10,340 patients who had both nancy rates to the comparator cohort (Fig. 3;[46]). appendectomy and tonsillectomy. The pregnancy rate Wei’s explanation for the association between appen- was 54.4% in the appendectomy-only cohort, 53.4% dectomy and increased pregnancy rate is that acute in the tonsillectomy-only cohort, and 59.7% in the co- abdominal pain in the right iliac fossa leading to ex- hort undergoing both surgeries, while in the compara-

Appendectomy and women’s reproductive outcomes K Review

tor cohort the pregnancy rate was 43.7% in a mean fol- Funding Open access funding provided by Università degli low-up of 14.7–9.7 years. Time to achieve pregnancy StudidiRomaLaSapienzawithintheCRUI-CAREAgreement. was shortest in patients who received both appendec- tomy and tonsillectomy, followed by patients who un- Declarations derwent appendectomy only, and then tonsillectomy Conflict of interest L. Merlino, A. Chiné, G. Carletti, F. Del only compared with the rest of the population [48]. Prete, M. Codacci Pisanelli, L. Titi, and M.G. Piccioni declare According to the authors, one possible explana- that they have no competing interests. tion for this phenomenon is that as any lymphoid Open Access This article is licensed under a Creative Com- organ, appendix and tonsils may be susceptible to mons Attribution 4.0 International License, which permits episodic, chronic, and/or recurrent inflammation, ei- use, sharing, adaptation, distribution and reproduction in ther de novo or after previous acute attacks [22, 24, any medium or format, as long as you give appropriate credit 27]. For this reason, by surgically removing these or- to the original author(s) and the source, provide a link to gans the degree of chronic inflammation and acute in- the Creative Commons licence, and indicate if changes were flammatory attacks can be hampered, resulting in im- made. The images or other third party material in this article proved wellbeing of young women, including a more are included in the article’sCreative Commons licence, unless indicated otherwise in a credit line to the material. If material favorable uterine, tubal, and ovarian environment for is not included in the article’s Creative Commons licence and pregnancy [48]. your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permis- Discussion sion directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Opinions in the literature regarding the consequences of appendicectomy on female fertility are conflicting. References Some authors believe that pelvic surgery can cause adhesions which can potentially lead to tubal infer- 1. Sudha G, Reddy KSN. Causes of female infertility: a cross- tility by causing tubal obstruction or by altering fim- sectionalstudy. IntJLatestResSciTechnol. 2013;2:119–23. brial motility, tubal fluid secretion, and embryo trans- 2. Deyhoul N, Mohamaddoost T, Hosseini M. Infertility-re- lated risk factors: a systematic review. Int J Womens Health port. On the other hand, the most recent evidence ReprodSci. 2017;5:24–9. reported that removal of the appendix seems to be 3. Templeton A. Infertility-epidemiology, aetiology and effec- associated with an increased pregnancy rate in large tivemanagement. HealthBull. 1995;53:294–8. population studies. The underlying pathophysiologi- 4. BehrmanSJ,Kistner RWA. Rationalapproachtotheevalua- cal mechanism by which this occurs must be further tion of infertility. In: Progress in infertility. 2nd ed. Boston: investigated, but an immunological process may be Little,Brown;1975. implicated. 5. Piccioni MG, Tabacco S, Merlino L, Del Negro V,Mazzeo A, Logoteta A, et al. Does hysterosalpingo-foam sonography have any therapeutic effect? A systematic review. Minerva Conclusion Ginecol. 2020;72(1):55–8. 6. Bellati F, Ruscito I, Gasparri ML, Antonilli M, Pernice M, Despite contrasting opinions in the literature con- Vallone C, et al. Effects of unilateral ovariectomy in female cerning fertility after appendectomy, the most recent fertility outcomes; gynecologic and repro- findings suggest that appendectomy may actually ductivemedicine. ArchGynecolObstet. 2014;290:349–53. 7. Practice Committee of the American Society for Reproduc- lead to improved fertility and to decreased time to tiveMedicineincollaborationwiththeSocietyofReproduc- pregnancy, thus suggesting that a more aggressive op- tive Surgeons. Pathogenesis, consequences, and control of erative approach in female patients of fertile age with peritoneal adhesionsingynaecologicsurgery: acommittee suspected appendicitis could be reasonable. More- opinion. FertilSteril. 2006;86(Suppl4):S1–S5. over, the minimally invasive laparoscopic approach 8. Bisset AF.Appendicectomy in Scotland: a 20-year epidemi- seems likely to reduce tissue trauma as well as scar ologicalcomparison. JPublicHealthMed. 1997;19:213–8. length, and consequently, by reducing the inflamma- 9. PrimatestaP,GoldacreMJ.Appendectomyforacuteappen- dicitis and for other conditions: an epidemiological study. tory process responsible for scarring and adhesions, IntJEpidemiol. 1994;23:155–60. might further minimize the negative impact of ap- 10. Donnelly NJ, Semmens JB, Fletcher DR, Holman CD. Ap- pendectomy on tubal fertility. pendicectomy in Western Australia: profile and trends, 1981–1997. MedJAust. 2001;175:15–8. Acknowledgements Thanks to Riccardo Carbonaro, MD, for 11. Wei L, MacDonald T, Shimi S. Association between ap- scientific contributions to the manuscript. pendicectomy in females and subsequent pregnancy rate: Author Contribution All authors read and approved the final acohortstudy. FertilSteril. 2012;98(2):401–5. version of the manuscript; Lucia Merlino: Conceptualization, 12. Lehmann-Willenbrocka EL, Meckea H, Riedel H-H. Se- methodology, writing; Alessandra Chiné: Data curation, writ- quelae of appendectomy, with special reference to intra- ing; Giulia Carletti: Data curation, writing; Federica Del Prete: abdominal adhesions, chronic abdominal pain, and infer- Conceptualization, methodology, writing; Massimo Codacci- tility. GynecolObstetInvest. 1990;29:241–5. Pisanelli: Supervision; Luca Titi: Visualization; Maria Grazia 13. Levrant SG, Bieber EJ, Barnes RB. Anterior abdominal wall Piccioni: Supervision. adhesions after laparotomy or laparoscopy. J Am Assoc GynecolLaparosc. 1997;4:353–6.

K Appendectomy and women’s reproductive outcomes Review

14. Lalos O. Risk factors for tubal infertility among infertile 36. Limberg J, Ginsburg H, Lala S, Tomita S. Recurrent pelvic and fertile women. Eur J Obstet Gynecol Reprod Biol. infections and salpingitis after appendicitis. J Pediatr 1988;29:129–36. AdolescGynecol. 2015;28(6):e177–e8. 15. Cromartie AD, Kovalcik PF. Previous appendectomy does 37. Vyas R, Sides C, Klein D, et al. The ectopic appendicolith not predispose to right-sided ectopic pregnancies. Arch from perforated appendicitis as a cause of tubo-ovarian Surg. 1978;113:905. abscess. PediatrRadiol. 2008;38:1006. 16. Nordenskjold F, Ahlgren M. Risk factors in ectopic preg- 38. Lundorff P, Hahlin M, Kallfelt B, Thorburn J, Lindblom B. nancy. Results of a population-based case-control study. Adhesion formation after laparoscopic surgery in tubal ActaObstetGynecolScand. 1991;70:575–9. pregnancy: a randomized trial versus laparotomy. Fertil 17. Michalas S, Minaretzis D, Tsionou C, Maos G, Kioses E, Steril. 1991;55:911–5. Aravantinos D. Pelvic surgery, reproductive factors and risk 39.DeWildeRL.Goodbyetolatebowelobstructionafter ofectopicpregnancy: acasecontrolledstudy.IntJGynaecol appendectomy. Lancet. 1991;338:1012. Obstet. 1992;38:101–5. 40.VrijlandWW,JeekelJ,vanGeldorpHJ,SwankDJ,BonjerHJ. 18. Thompson WM, Lynn HB. The possible relationship of Abdominal adhesions Intestinal obstruction, pain, and appendicitis with perforation in childhood to infertility in infertility. SurgEndosc. 2003;17(7):1017–22. women. JPediatrSurg. 1971;6:458–61. 41. Bruhat MA, Mage G, Manhes H, Pouly JL. Laparoscopy 19. Puri P,Guiney EJ, O’Donnell B, et al. Effects of perforated procedures to promote fertility ovariolysis and salpin- appendicitis in girls on subsequent fertility. Br Med J. golysis. Results of 93 selected cases. Acta Eur Fertil. 1984;288:25–6. 1983;14(2):113–5. 20. PuriP,McGuinnessEPJ,GuineyEJ.Fertilityfollowingperfo- 42. Surgical and Clinical Research (SCAR) Group, Lower AM, ratedappendicitisingirls. JPediatrSurg. 1989;24(6):547–9. Hawthorn RJ, Clark D, etal. Adhesion-relatedreadmissions 21. Forsell P,Pieper R. Infertility in young women due to perfo- following gynaecological laparoscopy or laparotomy in ratedappendicitis? ActaChirScandSuppl. 1986;530:59–60. Scotland: anepidemiologicalstudyof24046patients. Hum 22. Coste J, Job-Spira N, Fernandez H, et al. Risk factors Reprod. 2004;19:1877–85. for ectopic pregnancy: a case-control study in France, 43. VrijlandWW,TsengLNL,EijkmanHJM,HopWCJ,Jakimow- with special focus on infectious factors. Am J Epidemiol. icz JJ, Leguit P et al. Less intraperitoneal adhesions due 1991;133:839–49. to hyaluronic acid–carboxymethylcellulose membrane: 23. Andersson R, Lambe M, Bergstrom R. Fertility patterns arandomizedclinicaltrial. AnnSurg. 2002;235:193–9. after appendicectomy: historical cohort study. BMJ. 44. FarquharC,VandekerckhoveP,WatsonA,VailA,WisemanD. 1999;318:963–7. Barrier agents for preventing adhesions after surgery for 24.UrbachDR,MarrettLD,KungR,etal. Associationof subfertility. CochraneDatabaseSystRev. 2000; https://doi. perforationoftheappendixwithfemaletubalinfertility. Am org/10.1002/14651858.CD000475. JEpidemiol. 2001;153:566–71. 45. Canis M, Botchorishvili R, Bourdel N, Gremeau AS, 25. Powley PH. Infertility due to pelvic abscess and pelvic Curinier S, Rabischong B. Pelvic adhesions and fertility: peritonitisinappendicitis. Lancet. 1965;1:27–9. wherearewein2018? JViscSurg. 2018;155(Suppl1):S11–S5. 26. Geerdsen J, Hansen JB. Incidence of sterility in women 46. Lamps LW.Beyond acute inflammation: a review of appen- operated on in childhood for perforated appendicitis. Acta dicitis and infections of the appendix. Diagn Histopathol. ObstetGynecolScand. 1977;56:523–4. 2008;14(2):68–77. 27. Trimbos-KemperT,TrimbosB,vanHallE.Etiologicalfactors 47. Ekraiyah T, Hashim Y, Elamin M, Erwin PJ, Zarroug AE. intubalinfertility. FertilSteril. 1982;37:384–8. The effect of appendectomy in future tubal infertility and 28. Wiig JN, Janssen CW, Fuglesang P, et al. Infertility as ectopic pregnancy: a systematic review and meta-analysis. acomplicationofperforatedappendicitis: latefollow-upof JSurgRes. 2014;192(2):368–374.e1. aclinicalseries. ActaChirScand. 1979;145:409–10. 48. Wei L, MacDonald T, Shimi S. Association between prior 29. Mueller BA, Daling JR, Moore DE, et al. Appendectomy and appendectomy and/or tonsillectomy in women and sub- theriskoftubalinfertility. NEnglJMed. 1986;315:1506–8. sequent pregnancy rate: a cohort study. Fertil Steril. 30. Mastroianni L Jr. Tubal occlusion. In: Keller PJ, editor. 2016;106(5):1150–6. FemaleInfertility. Basel: Karger;1978. pp.114–31. 49. Rasmussen T,Fonnes S, Rosenberg J. Long-term complica- 31. Cloud DT. Appendicitis. In: Holder TM, Ashcraft KW, tions of appendectomy: a systematic review. Scand J Surg. editors. . Philadelphia: Saunders; 1980. 2018;107(3):189–96. p.506. 50. Arnbjornsson E. Relationship between the removal of the 32. Birkenfeld AS, Brzezinski A, Schenker JG. Post appen- non acute appendix and the menstrual cycle. Ann Chir dectomy mechanical sterility. Acta Eur Fertilitatis. Gynaecol. 1983;72:329–31. 1982;13:173–6. 51. ArnbjornssonE.Acuteappendicitisriskinvariousphasesof 33. Becker VM, Silver S, Seufert R, Muensterer JO. The Associ- themenstrualcycle. ActaChirScand. 1983;149:603–5. ation of Appendectomy, Adhesions, Tubal Pathology, and 52. Arnbjornsson E, Bengmark S. Obstruction of the appendix FemaleInfertility. JSLS. 2019;23(1):e2018.00099. lumen in relation to pathogenesis of acute appendicitis. 34. Singh-Ranger D, Sanusi A, Hamo I. Coliform pyosalpinx as ActaChirScand. 1983;149:789–91. a rare complication of appendectomy: a case report and review of the literature on best practice. J Med Case Rep. Publisher’s Note Springer Nature remains neutral with regard 2008;2:97. to jurisdictional claims in published maps and institutional 35. Niyogi A, Dalton J, Clarke S, et al. Recurrent unilateral affiliations. hydrosalpinx: a rare complication of acute perforated appendicitis. ArchGynecolObstet. 2009;280:835.

Appendectomy and women’s reproductive outcomes K