Recurrent Interstitial Pregnancy: a Review of the Literature

Interstitial pregnancy is a rare form of ectopic tubal pregnancy, accounting for 2 –4 % of all ectopic pregnancies. The terms cor- nual, interstitial and rarely angular ectopic pregnancy are often used synonymously. The true interstitial pregnancy is defined by its location lateral to the round ligament in the uterotubal junc- tion, whilst cornual and angular pregnancies are considered as in- trauterine pregnancies [1, 2]. Diagnosis is made by ultrasound and positive human chorionic gonadotropin (HCG) ( ▶ Fig. 1). Despite its rarity, there is a wide variety of treatment options but a lack of knowledge how recurrences might be prevented by the choice of treatment [1]. A literature search using PubMed and Google Scholar on recur- rent interstitial pregnancy reveals that only very few cases of re- Recurrent Interstitial Pregnancy: a Review of the Literature Wiederauftreten einer interstitiellen Schwangerschaft: eine Literaturübersicht Author Eva Egger 1, 2 Affiliations 1 University of Bonn, Department of Obstetrics and Gynecology/CIO, Bonn, Germany 2 Florence Nightingale Hospital, Department of Obstetrics and Gynecology, Düsseldorf, Germany Key words ectopic pregnancy, interstitial pregnancy, angular pregnancy, cornual pregnancy, recurrent ectopic pregnancy Schlüsselwörter ektope Schwangerschaft, interstitielle Schwangerschaft, anguläre Schwangerschaft, Uterushornschwangerschaft, erneute ektope Schwangerschaft received 21. 10. 2016 revised 19. 12. 2016 accepted 22. 12. 2016

DOI http://dx.doi.org/10.1055/s-0043-100107 Geburtsh Frauenheilk 2017; 77: 335 –339 © Georg Thieme Verlag KG Stuttgart · New York | ISSN 0016 ‑5751 Correspondence Dr. Eva Egger University of Bonn, Department of Obstetrics and Gynecology/CIO Sigmund-Freud-Straße 25, 53127 Bonn, Germany [email protected]

Interstitial pregnancies account for 2 –4 % of all ectopic pregnancies. Despite its rarity, various treatment options exist. However, no gold standard has yet been defined and data regarding recurrence of inter- stitial pregnancies in subsequent pregnancies after different treat- ments are sparse. This makes it very difficult to provide adequate pa- tient counselling for treatment options with regards to the treatment- related risk of recurrence. The present literature review demonstrates that recurrent interstitial pregnancy is a rare condition and more likely when additional anatomy-related risk factors for ectopic pregnancies are present, such as hydrosalpinges, blocked tubes, endometriosis, fibroids or prior tubal ectopic pregnancies. Therefore, at first appear- ance and in absence of additional anatomy-related risk factors, metho- trexate intravenously, intramuscularly or into the amnion may be the first choice. In case of anatomical risk factors, cornual wedge resection seems to be first choice. In case of recurrence, cornual wedge resec- tion is particularly justified in patients with anatomical alterations of the salpinges. The role of conservative surgical treatments in recur- rence as cornuotomy, salpingectomy, endoloop ligation and resection and curettage under laparoscopic guidance remains unclear due to sparse data. ZUSAMMENFASSUNG Nur circa 2 –4 % aller ektopen Graviditäten liegen interstitiell. Trotz ih- rer Seltenheit gibt es eine Reihe verschiedener Behandlungsoptionen. Aufgrund vieler Einzelfallberichte mit unterschiedlichen therapeuti- schen Herangehensweisen gibt es keinen Goldstandard und Daten zum Rezidivrisiko in Abhängigkeit zur gewählten Therapie fehlen. Das Rezidivrisiko ist für die adäquate Beratung der Patientin hinsichtlich ih- rer Therapiemöglichkeiten aber eine wichtige Information. Diese Lite- raturübersicht zeigt, dass eine wiederholt auftretende interstitielle Schwangerschaft selten ist. Die Wahrscheinlichkeit eines erneuten Auftretens ist höher bei Vorliegen zusätzlicher anatomischer Risikofak- toren für ektope Schwangerschaften, wie Hydrosalpinx, Tuben- obstruktion, Endometriose, Uterusmyome oder eine frühere ektope Tubargravidität. Bei Primärauftreten einer interstitiellen Schwanger- schaft und ohne Nachweis anatomischer Risikofaktoren erscheint eine medikamentöse Behandlung mit Methotrexat systemisch oder lokal zielführend. Bei Vorliegen von anatomischen Risikofaktoren und wei- terem Kinderwunsch sowie im Rezidivfall erscheint dagegen eine Keil- resektion des entsprechenden Uterushorns sinnvoll. Aufgrund der ein- geschränkten Datenlage und fehlender Studien bleibt der Stellenwert konservativer operativer Maßnahmen, wie die Uterushorneröffnung, die Salpingektomie, die Endoloop-Resektion bzw. die Kürettage unter laparoskopischer Kontrolle noch unklar. GebFra Science | Review 335Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339 current interstitial pregnancies have been reported. As detailed below, prior history and visible risk factors for ectopic pregnancies appear to be significant for the best choice of treatment. Literature Search A literature search in PubMed and Google Scholar was conducted by using the keywords “interstitial pregnancy ” or “cornual preg- nancy” or “angular pregnancy ”. Additionally, the references of pa- pers returned by this literature search were searched for further papers. The resulting abstracts were screened for information re- garding the further reproductive outcome. In total we found 61 articles on interstitial pregnancies where further information about the reproductive outcome after treatment could be re- trieved and 41 articles about interstitial pregnancies as heterotop- ic pregnancies where the further reproductive outcome was ad- dressed. Only 13 of these 102 publications were related to recur- rences of ipsilateral interstitial pregnancies. ▶ Table 1 shows the 13 case reports, with details presented on treatment, risk factors, time frame to recurrence and subsequent pregnancies. General Overview In the literature, recurrent interstitial pregnancy appears to be very rare. The only multiple case study of four cases [1] reported a prevalence of 0.3 % of all women with ectopic pregnancies over a five-year period. In the largest reported series of ectopic pregnan- cies [3], there was no recurrence of interstitial pregnancies re- ported with an overall rate of interstitial pregnancies of 2.4 %. All cases were treated by surgery. The majority of cases was treated by salpingectomy, which was considered a radical surgical ap- proach. Risk Factors In general, risk factors for an interstitial pregnancy and its recur- rence include 1. tubal anomaly, which can be induced by endometriosis or uter- ine leiomyomata, 2. anatomical damage due to pelvic inflammatory disease, 3. prior ectopic pregnancies, 4. salpingectomy and 5. assisted reproductive techniques. Eleven out of 17 cases of recurrent interstitial pregnancy showed at least one pathology or anatomical anomaly in the uterotubal junction [1, 2, 5, 11, 14, 16, 19, 20] ( ▶ Table 1). Furthermore, dam- aged tubes are found more frequently in proximal ectopic preg- nancies than in distal ectopic pregnancies [3]. Additionally, salpin- gectomy appears to be a singular predisposition for interstitial pregnancies as Simpson et al. showed in a literature review of 46 interstitial pregnancies after ipsilateral salpingectomy [4]. In the context of risk factors it is interesting to note that tubal occlusion within the uterotubal junction after recurrent interstitial pregnancy, which was treated twice with systemic methotrexate, eventually led to a successful intrauterine pregnancy [5]. Treatment Choice and Recurrence There are various treatment options. Conservative approaches in- clude methotrexate injections, which can be given systemically and/or locally. Tanaka reported in 1982 the first successful sys- temic methotrexate treatment of an interstitial pregnancy. He used 30 mg methotrexate intramuscularly on day 1, followed by two courses of 15 mg/d for a further five days. There were two days between the two courses [6]. The most common schedule is one or two courses with methotrexate 1 mg/kg/d systemically on day 1, 3, 5 and 7 with seven days in between. Different sched- ules also applied methotrexate locally in doses of 25 to 50 mg. The approximate overall success rate in various case reports is 83 %, while the local treatment was considered to be slightly more suc- cessful [7]. Importantly, randomized trials comparing treatment options regarding interstitial pregnancy are missing. The random- ized multicenter Demeter trial compared surgery with methotrex- ate 1 mg/kg/d on day 1, 4, 7, and 14 systemically in tubal ectopic pregnancies. The methotrexate schedule depended on the post- therapeutic HCG levels. While there was no significant difference regarding further fertility, the failure rate of systemic methotrex- ate was 21.8 % [8]. Within heterotopic pregnancies, defined by the coexistence of an intrauterine and an ectopic pregnancy, the co- existing interstitial pregnancy is often treated by a local potassium chloride injection. Surgical interventions, on the other hand, pri- marily take place in case of failure of local treatment [7, 11]. We only found one case of recurrence after treatment of a heterotop- ic pregnancy by selective fetocide of a heterotopic cornual preg- nancy by intracardial 0.5 ml 15 % KCL injection at 8 weeks of ges- tation. The remaining intrauterine pregnancy was uneventful and was delivered at term by a Caesarean section [11]. ▶ Fig. 1 Ultrasound picture of an interstitial pregnancy. 336 Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339 GebFra Science | Review ▶ Table 1 Reports about recurrent interstitial pregnancies. Author Prior obstetrical history Treatment first interstitial pregnancy Treatment recurrent interstitial pregancy Risk factors/ uterine/tubal pathologies Subsequent intrauterine pregnancy Time to recurrence (month) Sungurtekin and Uyar, 1998 [13] 2 SA Methotrexate 50 mg/d i. m. + citro- vorum factor 0.1 mg/kg for 5 days 1. 2 × Methotrexate 50 mg/d i. m. + citrovorum factor 0.1 mg/kg for 5 days, due to a viable pregnancy after the first course. 2. Laparotomy and resection of a uterine cornual mass, due to suspection of an imminent rupture. Pelvic endometriosis NO 17 Vilos, 2001 [2] 1 SA, 1 VD Laparoscopic ligation with endoloops and resection Laparoscopic ligation with endoloops and resection Bilateral intersti- tial-isthmic tubal anastomoses NO 10 Wittich, 1998 [14] 2V D 1C S Laparotomy + cornuostomy Laparotomy + cornual wedge resection PID, multiple leiomyomata NO 19 Budnick et al., 1993 [15] None Curettage under laparoscopic guidance Laparotomy + salpingectomy None MNS 8 Maruthini and Sharma, 2013 [16] None Laparotomy + cornuostomy + postoperatively methotrexate i. v. Laparotomy and diathermic coagulation Hydrosalpinges, bilateral salpin- gectomy, IVF CS 12 Sagiv et al., 2001 [10] None Laparoscopic methotrexate injection (12.5 mg) Laparoscopic cornuostomy None VD 6 Douysset et al., 2014 [17] NO Laparoscopic excision by Endo GIA stapling Laparotomy + cornuostomy NO NO NO Siow and Ng, 2011 [1] Pt 1: 2 EPT 1T E P Pt 2: 2 EPT Pt 3: 1 EPT Pt 4: 1 EPT Pt 1 + 2 Laparoscopic cornuostomy Pt 3 Uterine rupture, expellation by laparoscopic hydrodissection P t4Al e f t+r i g h t :l a p a r o s c o p i c wedge resection Pt 1–4: Laparoscopic wedge resection Pt 1: Previous tubal ectopic pregnancy Pt 3–4: PID Pt 4: IVF Pt 3: 1 VD, 2C S ,1E P T Pt 4: VD Pt 1: 18 Pt 2: 5 Pt 3: 26 Pt 4: 4/32 van der Weiden and Karsdorp, 2005 [11] None Selective fetocide of a heterotopic cornual pregnancy by intracardial 0.5 ml 15 % KCL injection at 8 weeks of gestation. CS of the intrauterine pregnancy at term. 0.5 ml 15 % KCL intracardial +4 0m gm e t h o t r e x a t ei nt h e gestational sac, 3 courses of methotrexate oral 1.0 mg/kg +1 5m gf o l i n i ca c i d IVF, blocked tubes NO 24 Faraj and Steel, 2008 [5] None Single dose systemic methotrexate Suction evacuation, without pregnancy products, 2 single doses of systemic methotrexate Abnormal shaped uterine cornu due to a fibroid At publication Pt. was preg- nant at 20 weeks of gestation after tubal occlusion 8 Hwang et al., 2011 [18] NO Cornual wedge resection Cornual wedge resection NO NO NO Faleyimu et al., 2008 [19] Laparotomy + cornual wedge resection Laparotomy with salpingo- oophorectomy Septic abortion in between both interstitial preg- nancies None 60 Sahoo et al., 2009 [20] 12 EG 3S A 1V D Laparoscopic endoloop resection of the ectopic pregnancy and dia- thermy, due to rising β‑HCG titers 600 mg mifepristone oral + 100 mg MTX i. m. was given. Laparoscopic right cornual excision by endoloop and diathermy. Hysteroscopy demonstrated the complete removal. 2 tubal ectopic pregnancies, right salpingec- tomy None 12 CS: Caesarean section, VD: vaginal delivery, MNS: mode of delivery not specified, NO: no information, EPT: early pregnancy termination, SA: spontan eous mis- carriages, PID: pelvic inflammatory disease, IVF: in vitro fertilisation. 337Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339 The main surgical options include salpingectomy, cornuotomy and cornual wedge resection ( ▶ Fig. 2). Regarding surgery one might expect cornual wedge resection as superior treatment and recurrent interstitial pregnancies to occur especially frequent after medical treatment, as only the cornual wedge resection, if done properly, will remove the uterotubal junction. In fact, we on- ly found two publications on a total of two patients with recur- rence after cornual wedge resection ( ▶ Table 1 ). Thirteen other patients recurred after being treated by various kinds of surgical techniques in their first interstitial pregnancy. In those 13 pa- tients, different surgical techniques were used. All of these proce- dures included at least the removal of pregnancy products and if necessary wound closure but excluded the resection of the entire uterotubal junctions as it is part of the cornual wedge resection ( ▶ Table 1 ). However, given the diversity of treatments and the very sparse data on their further outcomes, it is difficult to judge whether those different techniques may create a predisposition for recurrent interstitial pregnancy as the possible anatomical rea- son for interstitial pregnancy is not removed. Randomized trials regarding the quality of different surgical techniques are missing. Tubal Milieu In three cases, there was no known anatomical anomaly or tubal damage ( ▶ Table 1 ). In a further two cases, no information re- garding risk factors was available. In addition, only three publica- tions with recurrent interstitial pregnancy were found after prior medical treatment with systemic or local methotrexate injections. If anatomical alterations of the uterotubal junction as sequelace of conservative treatment of ectopic pregnancy would be the only reason for recurrence in interstitial pregnancies, one would have expected more case reports of recurrence [3, 5, 11]. Importantly, normal tubal function, which is needed for nor- mal intrauterine implantation, depends on more than anatomic normality. Modifications in tubal milieu may also lead to blasto- cyst arrest. By now it is understood that tubal functions like smooth muscle contractility and ciliary beat activity, which are of imminent importance for a later intrauterine implantation, are triggered through a wide range of different transmitters [3, 8]. Therefore, the conservative approach with systemic or local methotrexate injections may be justified, especially at first ap- pearance and in the absence of additional anatomy-related risk factors. Uterine Rupture The incidence of uterine ruptures in the scarred uterus appears to be low, but the fear of it remains and therefore medical treatment might be favored over cornual wedge resection [9]. Nevertheless, the actual risk of uterine rupture after medical treatment is un- known. Therefore, it is interesting to note that uterine rupture has been described in the unscarred uterus after interstitial preg- nancy. As in the recurrent interstitial pregnancy after hystero- scopic resection of the first interstitial pregnancy [15] and in the subsequent intrauterine pregnancy at 24 weeks of gestation after spontaneous resolution of an interstitial pregnancy by excision of a corpus luteum [21]. Surgical Approaches Regarding the chosen surgical approach – laparoscopy or laparot- omy – there seems to be no difference for later recurrences. As can be seen in ▶ Table 1 , seven patients recurred after laparos- copy and four patients recurred after laparotomy. Optimal sutur- ing and a very limited use of electrocautery might be of more im- portance when treating interstitial pregnancy surgically, regard- ing later uterine ruptures [1, 3, 12]. Timeframe and Subsequent Pregnancies The role of the variable timeframes to recurrence in all 16 cases, ranging from 5 to 60 months, and the significance of six subse- quent intrauterine pregnancies cannot be judged properly with regards to subsequent fertility or risk of recurrence, given that in- formation about contraception and try for pregnancy was not available. It is, however, interesting to note that two women had uneventful vaginal deliveries after cornual wedge resection and one after local methotrexate injection ( ▶ Table 1 ).

The literature review demonstrates that recurrent interstitial pregnancy is a very rare condition and more likely when additional anatomy-related risk factors for ectopic pregnancies are present, such as hydrosalpinges, blocked tubes, endometriosis, fibroids or prior tubal ectopic pregnancies. Nevertheless, it has to be ad- dressed when counseling patients for treatment options. Therefore, at first appearance and in absence of additional anatomy-related risk factors, local or systemic methotrexate in- ▶ Fig. 2 Interstitial pregnancy after cornual wedge resection. 338 Egger E Recurrent Interstitial Pregnancy: … Geburtsh Frauenheilk 2017; 77: 335 –339 GebFra Science | Review jections may be the first choice. In case of anatomical risk factors, cornual wedge resection seems to be the first choice. In case of recurrence, cornual wedge resection is particularly justified in pa- tients with anatomical alterations of the salpinges. Furthermore, surgery is needed to thoroughly inspect the anatomical condi- tions. The role of various other surgical treatments in recurrence, such as cornuotomy, salpingectomy, endoloop ligation and resec- tion and curettage under laparoscopic guidance remains unclear due to sparse data.

I would like to thank Prof. Herwig Egger and Prof. Walther C. Kuhn for helpful comments on an earlier version of this article. Conflict of Interest The author declares that she has no conflict of interests.

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