{"paper_id":"26f0a568-1747-419b-a53b-2c97b46db6cd","body_text":"Introduction\nInterstitial pregnancy is a rare form of ectopic tubal pregnancy,\naccounting for 2 –4 % of all ectopic pregnancies. The terms cor-\nnual, interstitial and rarely angular ectopic pregnancy are often\nused synonymously. The true interstitial pregnancy is defined by\nits location lateral to the round ligament in the uterotubal junc-\ntion, whilst cornual and angular pregnancies are considered as in-\ntrauterine pregnancies [1, 2]. Diagnosis is made by ultrasound and\npositive human chorionic gonadotropin (HCG) (\n▶ Fig. 1). Despite\nits rarity, there is a wide variety of treatment options but a lack of\nknowledge how recurrences might be prevented by the choice of\ntreatment [1].\nA literature search using PubMed and Google Scholar on recur-\nrent interstitial pregnancy reveals that only very few cases of re-\nRecurrent Interstitial Pregnancy: a Review of the Literature\nWiederauftreten einer interstitiellen Schwangerschaft:\neine Literaturübersicht\nAuthor\nEva Egger 1, 2\nAffiliations\n1 University of Bonn, Department of Obstetrics and Gynecology/CIO,\nBonn, Germany\n2 Florence Nightingale Hospital, Department of Obstetrics and\nGynecology, Düsseldorf, Germany\nKey words\nectopic pregnancy, interstitial pregnancy, angular pregnancy, cornual\npregnancy, recurrent ectopic pregnancy\nSchlüsselwörter\nektope Schwangerschaft, interstitielle Schwangerschaft, anguläre\nSchwangerschaft, Uterushornschwangerschaft, erneute ektope\nSchwangerschaft\nreceived 21. 10. 2016\nrevised 19. 12. 2016\naccepted 22. 12. 2016\nBibliography\nDOI http://dx.doi.org/10.1055/s-0043-100107\nGeburtsh Frauenheilk 2017; 77: 335 –339 © Georg Thieme Verlag KG\nStuttgart · New York | ISSN 0016 ‑5751\nCorrespondence\nDr. Eva Egger\nUniversity of Bonn, Department of Obstetrics and Gynecology/CIO\nSigmund-Freud-Straße 25, 53127 Bonn, Germany\neva.egger@gmx.de\nABSTRACT\nInterstitial pregnancies account for 2 –4 % of all ectopic pregnancies.\nDespite its rarity, various treatment options exist. However, no gold\nstandard has yet been defined and data regarding recurrence of inter-\nstitial pregnancies in subsequent pregnancies after different treat-\nments are sparse. This makes it very difficult to provide adequate pa-\ntient counselling for treatment options with regards to the treatment-\nrelated risk of recurrence. The present literature review demonstrates\nthat recurrent interstitial pregnancy is a rare condition and more likely\nwhen additional anatomy-related risk factors for ectopic pregnancies\nare present, such as hydrosalpinges, blocked tubes, endometriosis,\nfibroids or prior tubal ectopic pregnancies. Therefore, at first appear-\nance and in absence of additional anatomy-related risk factors, metho-\ntrexate intravenously, intramuscularly or into the amnion may be the\nfirst choice. In case of anatomical risk factors, cornual wedge resection\nseems to be first choice. In case of recurrence, cornual wedge resec-\ntion is particularly justified in patients with anatomical alterations of\nthe salpinges. The role of conservative surgical treatments in recur-\nrence as cornuotomy, salpingectomy, endoloop ligation and resection\nand curettage under laparoscopic guidance remains unclear due to\nsparse data.\nZUSAMMENFASSUNG\nNur circa 2 –4 % aller ektopen Graviditäten liegen interstitiell. Trotz ih-\nrer Seltenheit gibt es eine Reihe verschiedener Behandlungsoptionen.\nAufgrund vieler Einzelfallberichte mit unterschiedlichen therapeuti-\nschen Herangehensweisen gibt es keinen Goldstandard und Daten\nzum Rezidivrisiko in Abhängigkeit zur gewählten Therapie fehlen. Das\nRezidivrisiko ist für die adäquate Beratung der Patientin hinsichtlich ih-\nrer Therapiemöglichkeiten aber eine wichtige Information. Diese Lite-\nraturübersicht zeigt, dass eine wiederholt auftretende interstitielle\nSchwangerschaft selten ist. Die Wahrscheinlichkeit eines erneuten\nAuftretens ist höher bei Vorliegen zusätzlicher anatomischer Risikofak-\ntoren für ektope Schwangerschaften, wie Hydrosalpinx, Tuben-\nobstruktion, Endometriose, Uterusmyome oder eine frühere ektope\nTubargravidität. Bei Primärauftreten einer interstitiellen Schwanger-\nschaft und ohne Nachweis anatomischer Risikofaktoren erscheint eine\nmedikamentöse Behandlung mit Methotrexat systemisch oder lokal\nzielführend. Bei Vorliegen von anatomischen Risikofaktoren und wei-\nterem Kinderwunsch sowie im Rezidivfall erscheint dagegen eine Keil-\nresektion des entsprechenden Uterushorns sinnvoll. Aufgrund der ein-\ngeschränkten Datenlage und fehlender Studien bleibt der Stellenwert\nkonservativer operativer Maßnahmen, wie die Uterushorneröffnung,\ndie Salpingektomie, die Endoloop-Resektion bzw. die Kürettage unter\nlaparoskopischer Kontrolle noch unklar.\nGebFra Science | Review\n335Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339\n\n\ncurrent interstitial pregnancies have been reported. As detailed\nbelow, prior history and visible risk factors for ectopic pregnancies\nappear to be significant for the best choice of treatment.\nLiterature Search\nA literature search in PubMed and Google Scholar was conducted\nby using the keywords “interstitial pregnancy ” or “cornual preg-\nnancy” or “angular pregnancy ”. Additionally, the references of pa-\npers returned by this literature search were searched for further\npapers. The resulting abstracts were screened for information re-\ngarding the further reproductive outcome. In total we found 61\narticles on interstitial pregnancies where further information\nabout the reproductive outcome after treatment could be re-\ntrieved and 41 articles about interstitial pregnancies as heterotop-\nic pregnancies where the further reproductive outcome was ad-\ndressed. Only 13 of these 102 publications were related to recur-\nrences of ipsilateral interstitial pregnancies.\n▶ Table 1 shows the\n13 case reports, with details presented on treatment, risk factors,\ntime frame to recurrence and subsequent pregnancies.\nGeneral Overview\nIn the literature, recurrent interstitial pregnancy appears to be\nvery rare. The only multiple case study of four cases [1] reported\na prevalence of 0.3 % of all women with ectopic pregnancies over a\nfive-year period. In the largest reported series of ectopic pregnan-\ncies [3], there was no recurrence of interstitial pregnancies re-\nported with an overall rate of interstitial pregnancies of 2.4 %. All\ncases were treated by surgery. The majority of cases was treated\nby salpingectomy, which was considered a radical surgical ap-\nproach.\nRisk Factors\nIn general, risk factors for an interstitial pregnancy and its recur-\nrence include\n1. tubal anomaly, which can be induced by endometriosis or uter-\nine leiomyomata,\n2. anatomical damage due to pelvic inflammatory disease,\n3. prior ectopic pregnancies,\n4. salpingectomy and\n5. assisted reproductive techniques.\nEleven out of 17 cases of recurrent interstitial pregnancy showed\nat least one pathology or anatomical anomaly in the uterotubal\njunction [1, 2, 5, 11, 14, 16, 19, 20] (\n▶ Table 1). Furthermore, dam-\naged tubes are found more frequently in proximal ectopic preg-\nnancies than in distal ectopic pregnancies [3]. Additionally, salpin-\ngectomy appears to be a singular predisposition for interstitial\npregnancies as Simpson et al. showed in a literature review of 46\ninterstitial pregnancies after ipsilateral salpingectomy [4].\nIn the context of risk factors it is interesting to note that tubal\nocclusion within the uterotubal junction after recurrent interstitial\npregnancy, which was treated twice with systemic methotrexate,\neventually led to a successful intrauterine pregnancy [5].\nTreatment Choice and Recurrence\nThere are various treatment options. Conservative approaches in-\nclude methotrexate injections, which can be given systemically\nand/or locally. Tanaka reported in 1982 the first successful sys-\ntemic methotrexate treatment of an interstitial pregnancy. He\nused 30 mg methotrexate intramuscularly on day 1, followed by\ntwo courses of 15 mg/d for a further five days. There were two\ndays between the two courses [6]. The most common schedule\nis one or two courses with methotrexate 1 mg/kg/d systemically\non day 1, 3, 5 and 7 with seven days in between. Different sched-\nules also applied methotrexate locally in doses of 25 to 50 mg. The\napproximate overall success rate in various case reports is 83 %,\nwhile the local treatment was considered to be slightly more suc-\ncessful [7]. Importantly, randomized trials comparing treatment\noptions regarding interstitial pregnancy are missing. The random-\nized multicenter Demeter trial compared surgery with methotrex-\nate 1 mg/kg/d on day 1, 4, 7, and 14 systemically in tubal ectopic\npregnancies. The methotrexate schedule depended on the post-\ntherapeutic HCG levels. While there was no significant difference\nregarding further fertility, the failure rate of systemic methotrex-\nate was 21.8 % [8]. Within heterotopic pregnancies, defined by the\ncoexistence of an intrauterine and an ectopic pregnancy, the co-\nexisting interstitial pregnancy is often treated by a local potassium\nchloride injection. Surgical interventions, on the other hand, pri-\nmarily take place in case of failure of local treatment [7, 11]. We\nonly found one case of recurrence after treatment of a heterotop-\nic pregnancy by selective fetocide of a heterotopic cornual preg-\nnancy by intracardial 0.5 ml 15 % KCL injection at 8 weeks of ges-\ntation. The remaining intrauterine pregnancy was uneventful and\nwas delivered at term by a Caesarean section [11].\n▶ Fig. 1 Ultrasound picture of an interstitial pregnancy.\n336 Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339\nGebFra Science | Review\n\n\n▶ Table 1 Reports about recurrent interstitial pregnancies.\nAuthor Prior\nobstetrical\nhistory\nTreatment first interstitial\npregnancy\nTreatment recurrent interstitial\npregancy\nRisk factors/\nuterine/tubal\npathologies\nSubsequent\nintrauterine\npregnancy\nTime to\nrecurrence\n(month)\nSungurtekin and\nUyar, 1998 [13]\n2 SA Methotrexate 50 mg/d i. m. + citro-\nvorum factor 0.1 mg/kg for 5 days\n1. 2 × Methotrexate 50 mg/d i. m. +\ncitrovorum factor 0.1 mg/kg for\n5 days, due to a viable pregnancy\nafter the first course.\n2. Laparotomy and resection\nof a uterine cornual mass, due to\nsuspection of an imminent rupture.\nPelvic\nendometriosis\nNO 17\nVilos, 2001 [2] 1 SA, 1 VD Laparoscopic ligation with\nendoloops and resection\nLaparoscopic ligation with\nendoloops and resection\nBilateral intersti-\ntial-isthmic tubal\nanastomoses\nNO 10\nWittich, 1998\n[14]\n2V D\n1C S\nLaparotomy + cornuostomy Laparotomy + cornual wedge\nresection\nPID, multiple\nleiomyomata\nNO 19\nBudnick et al.,\n1993 [15]\nNone Curettage under laparoscopic\nguidance\nLaparotomy + salpingectomy None MNS 8\nMaruthini and\nSharma, 2013\n[16]\nNone Laparotomy + cornuostomy +\npostoperatively methotrexate i. v.\nLaparotomy and diathermic\ncoagulation\nHydrosalpinges,\nbilateral salpin-\ngectomy, IVF\nCS 12\nSagiv et al., 2001\n[10]\nNone Laparoscopic methotrexate\ninjection (12.5 mg)\nLaparoscopic cornuostomy None VD 6\nDouysset et al.,\n2014 [17]\nNO Laparoscopic excision\nby Endo GIA stapling\nLaparotomy + cornuostomy NO NO NO\nSiow and Ng,\n2011 [1]\nPt 1: 2 EPT\n1T E P\nPt 2: 2 EPT\nPt 3: 1 EPT\nPt 4: 1 EPT\nPt 1 + 2 Laparoscopic cornuostomy\nPt 3 Uterine rupture, expellation\nby laparoscopic hydrodissection\nP t4Al e f t+r i g h t :l a p a r o s c o p i c\nwedge resection\nPt 1–4: Laparoscopic wedge\nresection\nPt 1: Previous\ntubal ectopic\npregnancy\nPt 3–4: PID\nPt 4: IVF\nPt 3: 1 VD,\n2C S ,1E P T\nPt 4: VD\nPt 1: 18\nPt 2: 5\nPt 3: 26\nPt 4: 4/32\nvan der Weiden\nand Karsdorp,\n2005 [11]\nNone Selective fetocide of a heterotopic\ncornual pregnancy by intracardial\n0.5 ml 15 % KCL injection at 8 weeks\nof gestation. CS of the intrauterine\npregnancy at term.\n0.5 ml 15 % KCL intracardial\n+4 0m gm e t h o t r e x a t ei nt h e\ngestational sac, 3 courses of\nmethotrexate oral 1.0 mg/kg\n+1 5m gf o l i n i ca c i d\nIVF, blocked tubes NO 24\nFaraj and Steel,\n2008 [5]\nNone Single dose systemic methotrexate Suction evacuation, without\npregnancy products, 2 single doses\nof systemic methotrexate\nAbnormal shaped\nuterine cornu\ndue to a fibroid\nAt publication\nPt. was preg-\nnant at 20\nweeks of\ngestation after\ntubal occlusion\n8\nHwang et al.,\n2011 [18]\nNO Cornual wedge resection Cornual wedge resection NO NO NO\nFaleyimu et al.,\n2008 [19]\nLaparotomy + cornual wedge\nresection\nLaparotomy with salpingo-\noophorectomy\nSeptic abortion\nin between both\ninterstitial preg-\nnancies\nNone 60\nSahoo et al.,\n2009 [20]\n12 EG\n3S A\n1V D\nLaparoscopic endoloop resection\nof the ectopic pregnancy and dia-\nthermy, due to rising β‑HCG titers\n600 mg mifepristone oral + 100 mg\nMTX i. m. was given.\nLaparoscopic right cornual excision\nby endoloop and diathermy.\nHysteroscopy demonstrated the\ncomplete removal.\n2 tubal ectopic\npregnancies,\nright salpingec-\ntomy\nNone 12\nCS: Caesarean section, VD: vaginal delivery, MNS: mode of delivery not specified, NO: no information, EPT: early pregnancy termination, SA: spontan eous mis-\ncarriages, PID: pelvic inflammatory disease, IVF: in vitro fertilisation.\n337Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339\n\n\nThe main surgical options include salpingectomy, cornuotomy\nand cornual wedge resection ( ▶ Fig. 2). Regarding surgery one\nmight expect cornual wedge resection as superior treatment and\nrecurrent interstitial pregnancies to occur especially frequent\nafter medical treatment, as only the cornual wedge resection, if\ndone properly, will remove the uterotubal junction. In fact, we on-\nly found two publications on a total of two patients with recur-\nrence after cornual wedge resection (\n▶ Table 1 ). Thirteen other\npatients recurred after being treated by various kinds of surgical\ntechniques in their first interstitial pregnancy. In those 13 pa-\ntients, different surgical techniques were used. All of these proce-\ndures included at least the removal of pregnancy products and if\nnecessary wound closure but excluded the resection of the entire\nuterotubal junctions as it is part of the cornual wedge resection\n(\n▶ Table 1 ). However, given the diversity of treatments and the\nvery sparse data on their further outcomes, it is difficult to judge\nwhether those different techniques may create a predisposition\nfor recurrent interstitial pregnancy as the possible anatomical rea-\nson for interstitial pregnancy is not removed. Randomized trials\nregarding the quality of different surgical techniques are missing.\nTubal Milieu\nIn three cases, there was no known anatomical anomaly or tubal\ndamage (\n▶ Table 1 ). In a further two cases, no information re-\ngarding risk factors was available. In addition, only three publica-\ntions with recurrent interstitial pregnancy were found after prior\nmedical treatment with systemic or local methotrexate injections.\nIf anatomical alterations of the uterotubal junction as sequelace of\nconservative treatment of ectopic pregnancy would be the only\nreason for recurrence in interstitial pregnancies, one would have\nexpected more case reports of recurrence [3, 5, 11].\nImportantly, normal tubal function, which is needed for nor-\nmal intrauterine implantation, depends on more than anatomic\nnormality. Modifications in tubal milieu may also lead to blasto-\ncyst arrest. By now it is understood that tubal functions like\nsmooth muscle contractility and ciliary beat activity, which are of\nimminent importance for a later intrauterine implantation, are\ntriggered through a wide range of different transmitters [3, 8].\nTherefore, the conservative approach with systemic or local\nmethotrexate injections may be justified, especially at first ap-\npearance and in the absence of additional anatomy-related risk\nfactors.\nUterine Rupture\nThe incidence of uterine ruptures in the scarred uterus appears to\nbe low, but the fear of it remains and therefore medical treatment\nmight be favored over cornual wedge resection [9]. Nevertheless,\nthe actual risk of uterine rupture after medical treatment is un-\nknown. Therefore, it is interesting to note that uterine rupture\nhas been described in the unscarred uterus after interstitial preg-\nnancy. As in the recurrent interstitial pregnancy after hystero-\nscopic resection of the first interstitial pregnancy [15] and in the\nsubsequent intrauterine pregnancy at 24 weeks of gestation after\nspontaneous resolution of an interstitial pregnancy by excision of\na corpus luteum [21].\nSurgical Approaches\nRegarding the chosen surgical approach – laparoscopy or laparot-\nomy – there seems to be no difference for later recurrences. As\ncan be seen in ▶ Table 1 , seven patients recurred after laparos-\ncopy and four patients recurred after laparotomy. Optimal sutur-\ning and a very limited use of electrocautery might be of more im-\nportance when treating interstitial pregnancy surgically, regard-\ning later uterine ruptures [1, 3, 12].\nTimeframe and Subsequent Pregnancies\nThe role of the variable timeframes to recurrence in all 16 cases,\nranging from 5 to 60 months, and the significance of six subse-\nquent intrauterine pregnancies cannot be judged properly with\nregards to subsequent fertility or risk of recurrence, given that in-\nformation about contraception and try for pregnancy was not\navailable. It is, however, interesting to note that two women had\nuneventful vaginal deliveries after cornual wedge resection and\none after local methotrexate injection (\n▶ Table 1 ).\nConclusions\nThe literature review demonstrates that recurrent interstitial\npregnancy is a very rare condition and more likely when additional\nanatomy-related risk factors for ectopic pregnancies are present,\nsuch as hydrosalpinges, blocked tubes, endometriosis, fibroids or\nprior tubal ectopic pregnancies. Nevertheless, it has to be ad-\ndressed when counseling patients for treatment options.\nTherefore, at first appearance and in absence of additional\nanatomy-related risk factors, local or systemic methotrexate in-\n▶ Fig. 2 Interstitial pregnancy after cornual wedge resection.\n338 Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339\nGebFra Science | Review\n\n\njections may be the first choice. In case of anatomical risk factors,\ncornual wedge resection seems to be the first choice. In case of\nrecurrence, cornual wedge resection is particularly justified in pa-\ntients with anatomical alterations of the salpinges. Furthermore,\nsurgery is needed to thoroughly inspect the anatomical condi-\ntions. The role of various other surgical treatments in recurrence,\nsuch as cornuotomy, salpingectomy, endoloop ligation and resec-\ntion and curettage under laparoscopic guidance remains unclear\ndue to sparse data.\nAcknowledgements\nI would like to thank Prof. Herwig Egger and Prof. Walther C. Kuhn\nfor helpful comments on an earlier version of this article.\nConflict of Interest\nThe author declares that she has no conflict of interests.\nReferences\n[1] Siow A, Ng S. Laparoscopic management of 4 cases of recurrent cornual\nectopic pregnancy and review of literature. J Minim Invasive Gynecol\n2011; 18: 296 –302\n[2] Vilos GA. Laparoscopic ligation and resection of two ipsilateral intersti-\ntial pregnancies in the same patient. J Am Assoc Gynecol Laparosc\n2001; 8: 299 –302\n[3] Bouyer J, Coste J, Fernandez H et al. Sites of ectopic pregnancy: a 10 year\npopulation-based study of 1800 cases. Hum Reprod 2002; 17: 3224 –\n3230\n[4] Simpson J, Alford C, Miller A. Interstitial pregnancy following homolater-\nal salpingectomy. A report of 6 new cases and review of the literature.\nAm J Obstet Gynecol 1961; 82: 1173 –1179\n[5] Faraj R, Steel M. Can we reduce the recurrence of cornual pregnancy? A\ncase report. Gynecol Surg 2008; 6: 57 –59\n[6] Tanaka T, Hayashi H, Kutsuzawa T et al. Treatment of interstitial ectopic\npregnancy with methotrexate: report of a successful case. Fertil Steril\n1982; 37: 851 –852\n[7] Lau S, Tulandi T. Conservative medical and surgical management of in-\nterstitial ectopic pregnancy. Fertil Steril 1999; 72: 207 –215\n[8] Fernandez H, Capmas P, Lucot JP et al.; GROG. Fertility after ectopic\npregnancy: the DEMETER randomized trial. Hum Reprod 2013; 28:\n1247–1253\n[9] Vandenberghe G, De Blaere M, Van Leeuw V et al. Nationwide popula-\ntion-based cohort study of uterine rupture in Belgium: results from the\nBelgian Obstetric Surveillance System. BMJ Open 2016; 6: e010415\n[10] Sagiv R, Golan A, Arbel-Alon S et al. Three conservative approaches to\ntreatment of interstitial pregnancy. J Am Assoc Gynecol Laparosc 2001;\n8: 154 –158\n[11] van der Weiden RM, Karsdorp VH. Recurrent cornual pregnancy after\nheterotopic cornual pregnancy successfully treated with systemic me-\nthotrexate. Arch Gynecol Obstet 2005; 273: 180 –181\n[12] Shaw JL, Dey SK, Critchley HO et al. Current knowledge of the aetiology\nof human tubal ectopic pregnancy. Hum Reprod Update 2010; 16: 432 –\n444\n[13] Sungurtekin U, Uyar Y. Recurrent interstitial pregnancy. Aust N Z J Ob-\nstet Gynaecol 1998; 38: 438 –440\n[14] Wittich AC. Recurrent cornual ectopic pregnancy in a patient with leio-\nmyomata uteri. J Am Osteopath Assoc 1998; 98: 332 –333\n[15] Budnick SG, Jacobs SL, Nulsen JC et al. Conservative management of in-\nterstitial pregnancy. Obstet Gynecol Surv 1993; 48: 694 –698\n[16] Maruthini D, Sharma V. A case of live birth after uterine reconstruction\nfor recurrent cornual ectopic pregnancy following IVF treatment. Case\nRep Obstet Gynecol 2013; 2013: 625261\n[17] Douysset X, Verspyck E, Diguet A et al. [Interstitial pregnancy: experi-\nence at Rouen ʼs hospital]. Gynecol Obstet Fertil 2014; 42: 216 –221\n[18] Hwang JH, Lee JK, Lee NW et al. Open cornual resection versus laparo-\nscopic cornual resection in patients with interstitial ectopic pregnancies.\nEur J Obstet Gynecol Reprod Biol 2011; 156: 78 –82\n[19] Faleyimu BL, Igberase GO, Momoh MO. Ipsilateral ectopic pregnancy oc-\ncurring in the stump of a previous ectopic site: a case report. Cases J\n2008; 1: 343\n[20] Sahoo S, Jose J, Shah N et al. Recurrent cornual ectopic pregnancies. Gy-\nnecol Surg 2009; 6: 389 –391\n[21] Downey GP , Tuck SM. Spontaneous uterine rupture during subsequent\npregnancy following non-excision of an interstitial ectopic gestation. Br\nJ Obstet Gynaecol 1994; 101: 162 –163\n339Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339","source_license":"CC0","license_restricted":false}