Ectopic pregnancies of unusual location: management dilemmas

Ultrasound Obstet Gynecol 2008; 31: 245–251 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5277

Editorial Ectopic pregnancies of unusual location: management dilemmas D. V. VALSKY and S. YAGEL Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Centers, Mt. Scopus, Jerusalem, Israel (e-mail: [email protected])

Introduction Ectopic pregnancy is a diagnostic and management challenge. Advances in ultrasound technology and operator expertise have provided the capability to visualize ectopic pregnancy at its earliest stages. While tubal ectopic pregnancies are still the most commonly seen1 – 3 , the increased use of assisted reproduction techniques has been accompanied by an increase in ectopic pregnancies of unusual location (Figure 1), and the rise in Cesarean deliveries has been accompanied by a rise in pregnancies implanted in the Cesarean scar. These trends have been noted and reviewed in the literature and the sonographic diagnostic criteria of the various types of ectopic pregnancy have been illustrated1 – 3 . However, sparse evidence has accrued in the literature to guide management decisions when ectopic pregnancy is diagnosed. There are three basic management approaches to ectopic pregnancy: expectant management, medical treatment administered systemically or locally, and surgical intervention, including laparotomy, laparoscopy, hysteroscopy, and dilatation and curettage (D&C). In recent years uterine artery embolization (UAE) has become more common, at times being applied as a first-line treatment, but more often being used as a rescue procedure in cases of treatment failure and hemorrhage4 – 8 . In this light, we summarize in this Editorial what is known regarding the outcomes of each approach, in interstitial, cervical and Cesarean scar ectopic pregnancies. We do not address the issues surrounding ovarian and abdominal ectopic pregnancies due to their extreme rarity. Our purpose is to summarize the evidence available to support management options for these ectopic pregnancies of unusual location, to describe the dilemmas that may arise, and to suggest strategies to improve the evidence base and ultimately to develop guidelines for the management of these challenging cases.

Interstitial and cornual pregnancy Case presentation A 28-year-old woman who had undergone bilateral salpingectomy was referred with a suspected heterotopic

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pregnancy 4 weeks after in-vitro fertilization (IVF). On presentation she was asymptomatic. Sonographic evaluation on admission revealed a heterotopic pregnancy with intrauterine and left interstitial gestational sacs (Figure 2). The ectopic sac was non-viable and expectant management was planned. Laparoscopy with excision of the interstitial pregnancy was performed (Videoclip S1, online) on the development of pain and suspected intra-abdominal bleeding. The intrauterine pregnancy continued and a normal infant weighing 2565 g was delivered at 35 + 5 gestational weeks by Cesarean section. Analysis Interstitial pregnancy occurs when the gestational sac is implanted in the portion of the Fallopian tube within the muscular wall of the uterus. This highly vascularized area has great potential for severe hemorrhage in the case of perforation. Two-dimensional (2D) ultrasound-based criteria for the diagnosis of interstitial pregnancy have been proposed9,10 , but misdiagnosis is still common10 . An interstitial pregnancy is diagnosed when a regular

Figure 1 Three-dimensional ultrasound image using VCI-C (volume contrast imaging in the C-plane) acquisition mode in a woman with heterotopic intrauterine (IUP) and interstitial (IP) pregnancies, showing the two gestational sacs with fetal pole. The uterine fundus is indicated ( ) as well as the demarcation of the endometrial border (arrow).

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Figure 2 (a) Rendered image from static three-dimensional ultrasound acquisition of the coronal plane of the uterus in a woman with intrauterine (G) and interstitial (IP) gestational sacs. Arrows indicate the border of the endometrium and the myometrial layer is denoted M. Interstitial pregnancy is diagnosed when a regular endometrium without visible gestational sac or mass is visualized, and the gestational sac is located outside the endometrium and surrounded by a continuous rim of myometrium, within the interstitial area1 . (b) Image obtained at laparoscopy showing the protrusion of the ectopic gestational sac and active bleeding ( ). (See also supplementary material online: Videoclip S1).

endometrium without visible gestational sac or mass is visualized, and a gestational sac is located outside the endometrium and surrounded by a continuous rim of myometrium, within the interstitial area. A pregnancy is defined as cornual when it is situated in the uterine cavity but asymmetrically in the cornu, medial to the round ligament1 . In the English literature, these definitions are sometimes used interchangeably, although different clinical courses have been described1,2 . The use of threedimensional (3D) ultrasound, with its capability to image the coronal plane of the uterus, can have added value in the diagnosis of cornual and interstitial ectopic pregnancies11 . Expectant management of interstitial pregnancy may be possible with close monitoring for falling beta-human chorionic gonadotropin (β-hCG) levels and shrinking gestational mass. The follow-up period for expectantly managed cases can be very long; a sonographically visible mass can persist for many weeks. These findings can be densely vascular (Figure 3) and raise the dilemma as to whether to continue waiting with close monitoring or to intervene. If the patient is asymptomatic and β-hCG levels are falling, patience and a long follow-up are appropriate. Systemic medical management has been reported in these cases. A single dose of methotrexate (MTX) is usually sufficient, with a second dose required only in a minority of cases if β-hCG levels do not fall10 . In their review of 65 cases of conservatively managed interstitial pregnancy, Jermy et al. found the overall success rate of systemic MTX treatment (of varying one- or multi-dose regimens) to be 40/45 (88%)10 . One case required a local injection of MTX as well. Local medical management involves ultrasound-guided injection of MTX into the gestational sac. If cardiac


activity is present, potassium chloride (KCl) may be administered intra-amniotically. In cases of heterotopic interstitial pregnancy, KCl administered exclusively to the ectopic gestational sac can be particularly effective3,10 . Technical issues of local injection, however, may preclude this therapy in some cases. The review of 65 cases by Jermy et al. found the success rate of local MTX injection to be 19/20 (95%), although one patient required laparoscopy for hemostasis10 . As for expectant management, a long period of close monitoring is required following medical therapy in these cases, until full sonographic resolution is observed. Surgical management usually involves cornual resection or hysterectomy at laparotomy. Minimally invasive procedures such as laparoscopy are becoming more common. This approach requires technical skill and carries a risk of hemorrhage. As this management option becomes available in more centers and more evidence is accrued, it may be found to be suitable in symptomatic women, while laparotomy will be reserved for acute, actively bleeding cases.

Cervical pregnancy Case presentation A 27-year-old woman, whose history included two pregnancy terminations, presented for a routine dating scan at 8 weeks’ amenorrhea. Ultrasound examination revealed a gestational sac with a viable fetus in the uterine cervix. She was treated with intra-amniotic KCl and local MTX injection. Two days following the procedure she returned with severe vaginal bleeding. Curettage was

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Figure 3 Series of three-dimensional (3D) ultrasound images in a woman with interstitial pregnancy managed conservatively. (a) Multiplanar 3D static imaging (coronal plane) of the uterus at presentation, showing the non-viable left interstitial gestational sac. The patient was asymptomatic with a beta-human chorionic gonadotropin (β-hCG) level of 750 mIU/mL. (b) Rendered image on day 52 from static 3D acquisition, showing the highly vascularized area (arrow) indicative of the changes in the endometrium at the area of implantation of the gestational sac. The patient’s β-hCG at this visit was 75 mIU/mL. (c) VCI-C (volume contrast imaging in the C-plane) acquisition on day 69: the vascularized area was still visible. (d) Nearly 4 months following presentation, this rendered 3D ultrasound image showed complete resolution; the normal uterine cornu is demonstrated ( ).

attempted but the bleeding intensified. Bilateral UAE was performed and the bleeding abated. Analysis Cervical pregnancy is diagnosed when the entire gestational sac, having a well-formed shape, is


demonstrated in the dilated cervix. The sac may contain a yolk sac and embryo, with or without cardiac activity, located below the level of the internal os. Except in the case of heterotopic pregnancy, the endometrial stripe is visualized and an hourglass shape of the uterus is evident. Color Doppler scanning is useful in differentiating between inevitable miscarriage of a gestational sac in the


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cervix and true cervical pregnancy. In true cervical pregnancy, Doppler studies show characteristic patterns of trophoblast with high flow velocity and low impedance, while in miscarriage the sac will be mobile, with no Doppler evidence of blood flow1,2 . Expectant management of cervical pregnancy is usually not an option, though it has been described12 . Conservative management is possible if it is diagnosed early, as described for interstitial pregnancy. In a review of 90 cases of conservative management of cervical pregnancy, which included both systemic and local injection of MTX and/or KCl, 61 (78%) cases were

Valsky and Yagel successful and reached full resolution, while 19 required intervention, including insertion of a Shirodkar suture, UAE or Foley catheter balloon tamponade. Thirty-two patients were also treated with curettage. Three patients required hysterectomy12 . The surgical management of interstitial and Cesarean scar pregnancies essentially involves excision of the gestational sac, but this is not possible in the case of cervical pregnancy. The anatomy of the cervix makes it prone to hemorrhage as trophoblast is sloughed. So, while these pregnancies are candidates for conservative management to preserve fertility, they may often require

Figure 4 (a) Three-dimensional ultrasound image using VCI-C (volume contrast imaging in the C-plane) showing the coronal plane of the uterus in a woman with Cesarean scar defect ( ). In (b), the fluid-filled area of the scar defect (1.7 × 1.0 cm) is visible in the anterior wall of the uterus; the uterine wall defect (measurement 1) was 0.42 cm in length. (c) Rendered sagittal image showing the cervix (cx), the endocervical canal ( ), the scar defect in the anterior uterine wall (arrow) and the bladder (bl).



Editorial intervention to stop hemorrhage. Having recently gained acceptance in gynecological surgery4 , UAE, which aims to slow hemorrhage by limiting blood supply to the uterus, has been applied in the management of cervical pregnancy as adjunctive treatment to control hemorrhage following local or systemic MTX administration, and as primary intervention in missed cervical pregnancies to prevent excessive bleeding as the pregnancy resolves5 .

Cesarean scar pregnancy Case presentation A 39-year-old woman was diagnosed with a uterine wall defect of 4 mm at the Cesarean scar site during routine pelvic ultrasound examination (Figure 4). She was later referred for investigation of suspected Cesarean scar pregnancy, which revealed a non-viable 5-cm gestational sac located within the isthmic area of the lower anterior wall of the uterus, protruding toward the vesicouterine junction (Figure 5, Videoclip S2). Conservative management was planned; however, on the development of severe vaginal bleeding the patient was readmitted and D&C performed. Bleeding continued and disseminated intravascular coagulation developed. The patient received repeated blood transfusions, laparotomy was performed and the gestational sac was resected (Videoclip S2, online). Refractory uterine bleeding necessitated intracavitary Foley balloon tamponade. Analysis Sonographic evidence of a defect in the area of a Cesarean scar can theoretically be diagnosed in all women who have undergone this procedure, whether they are symptomatic or asymptomatic13 – 15 . There are no strict diagnostic

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criteria for uterine wall defect at the Cesarean scar site, although fluid collection in the scar area14 or detectable myometrial thinning at the scar site15 have been proposed. Criteria for the sonographic diagnosis of Cesarean scar pregnancy have been proposed16 . The spectrum of management strategies for Cesarean scar pregnancy is broad, and has been presented in several case series and recent reviews17 – 21 . Expectant management has been described, but it carries a considerable risk of uterine rupture and hemorrhage19 , perhaps as high as 50%. Asymptomatic and hemodynamically stable patients are candidates for medical management. Systemic therapy consists of different regimens (single or repeated doses) of MTX treatment. This has been described for asymptomatic patients with unruptured pregnancies of less than 8 weeks and β-hCG < 5000 mIU/mL17,19 . The success rate of this approach is difficult to determine, partly due to publication bias of case reports and also due to the tendency to resort to surgery on the first suspicion of complications22 , but it has been estimated at between 44 and 80%19 . The actual success rate is probably somewhat more modest. Local therapy involves injection of MTX directly into the gestational sac. This may be appropriate when β-hCG levels are high. Additional doses may be needed if the gestational sac persists or excessive bleeding ensues. In some cases, systemic and local MTX may be combined19 . Surgical interventions that have been applied include endoscopic methods (hysteroscopy or laparoscopy) and laparotomy, which involves a wedge-shaped excision of the gestational tissue and repair of the uterine wall defect23 . This may be advantageous for subsequent pregnancies. The procedure has a short immediate follow-up period, but full recovery to disappearance of residua may be lengthy. Endoscopic surgical methods have the advantage of being minimally invasive while still providing a definitive treatment. However, this approach is most suitable when experienced surgical and support systems are available, for example angiography for prompt and effective hemostasis. No formal data are available on the role of angiography in the armamentarium of scar pregnancy treatment procedures. D&C should not be considered, as it has been shown to have a high failure rate and may result in severe hemorrhage19 , necessitating urgent complimentary treatment procedures.

Discussion

Figure 5 Cesarean scar pregnancy in the same woman as in Figure 4. The gestational sac (sac) was located within the isthmic area of the lower anterior wall of the uterus, protruding towards the vesicouterine junction. The endometrium is indicated ( ), as are the uterine–bladder interface (arrow), the cervix (cx) and the uterus (u). (See also supplementary material online: Videoclip S2).


There have been no prospective studies to compare outcomes of medical and surgical management strategies for ectopic pregnancies of unusual location. Conservative management approaches have been proposed in recent years. The published case reports and case series describe women observed in the authors’ centers and treated with various regimens of MTX, KCl or other agents. Patient selection is not standardized regarding level of β-hCG, gestational age, size of gestational sac or mass, or presence


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Figure 6 A large Cesarean scar defect in the anterior wall ( ) of a non-gravid uterus, as demonstrated by: two-dimensional sagittal transvaginal ultrasound (a); multiplanar imaging (b); and the rendered image of the defect, enlarged (c). The patient presented for investigation of persistent uterine bleeding 2 months following Cesarean delivery.

or absence of cardiac activity. The definitions of treatment success or failure are not uniform; nor are the approaches to treatment failure. Follow-up periods also vary greatly, since conservative management often requires lengthy follow-up until the disappearance of sonographic evidence of the gestational tissue. Data regarding the future obstetric success of medically treated patients are also lacking. This is particularly important regarding patients with interstitial or cornual pregnancy. It is unknown how the management of these pregnancies will affect their future risks at delivery, or, if they are managed surgically, whether they should be delivered by elective Cesarean in subsequent pregnancies, or whether they could be delivered vaginally. Many questions surround each type of ectopic pregnancy of unusual location. In interstitial pregnancy, for example, is intervention necessary in a missed abortion? How long is too long for a wait-and-see approach? What is the risk of bleeding if the sac is not developing? Can we base the decision on the size of the mass, gestational age or β-hCG? As laparoscopy becomes more commonly employed, what is its real-world success rate? How should we regard the post-laparoscopic uterus? Is the uterus scarred, and if so should these women be considered at high risk of rupture and delivered by Cesarean? No study has compared outcomes of laparoscopy and laparotomy with respect to immediate outcome or long-term follow-up and risks. While our skills in diagnosis and follow-up have increased, our ability to counsel the patient, especially regarding her obstetric future, has not kept pace. In cervical ectopic pregnancy, our surgical management options are more limited because of the problematic location. D&C can be very dangerous and hysteroscopy is not feasible. These baseline limitations place much more weight on alternative treatments, such as UAE, but there are no clear-cut criteria for patient selection for this procedure. Should UAE be considered as a firstline treatment option in cervical pregnancy, or reserved as a rescue procedure in cases of hemorrhage? When do we intervene surgically in these cases? If a cervical pregnancy is non-viable and the patient is asymptomatic, can we wait? Where there are no clear criteria, should the


decision be based on gestational age, β-hCG levels or the size of the mass? In the case of Cesarean scar pregnancies, it is possible to diagnose a uterine scar defect in the non-gravid uterus (Figure 6). In this instance should the defect be repaired? Is the defect’s size of any significance in taking this step? Will repair prevent some or any Cesarean scar pregnancies? Many cases of conservative management of ectopic pregnancies have been described in the literature. It is time to move forward with the tools that we have to develop strategies to address the management dilemmas described here. The time has come for structured studies that will allow for the objective comparison of surgical and medical approaches to these cases. As the conditions described here are rare, no single center can collect sufficient cases for a well-powered study. We propose that management protocols be developed, so that in time it will be possible to collect, analyze and compare successfully managed and complicated cases, to create an evidentiary basis for patient counseling and management.

REFERENCES 1. Jurkovic D, Mavrelos D. Catch me if you scan: ultrasound diagnosis of ectopic pregnancy. Ultrasound Obstet Gynecol 2007; 30: 1–7. 2. Lemus JF. Ectopic pregnancy: an update. Curr Opin Obstet Gynecol 2000; 12: 369–75. 3. Kirk E, Bourne T. The nonsurgical management of ectopic pregnancy. Curr Opin Obstet Gynecol 2006; 18: 587–93. 4. Badawy SZ, Etman A, Singh M, Murphy K, Mayelli T, Philadelphia M. Uterine artery embolization: the role in obstetrics and gynecology. Clin Imaging 2001; 25: 288–95. 5. Takano M, Hasegawa Y, Matsuda H, Kikuchi Y. Successful management of cervical pregnancy by selective uterine artery embolization: a case report. J Reprod Med 2004; 49: 986–8. 6. Deruelle P, Lucot JP, Lions C, Robert Y. Management of interstitial pregnancy using selective uterine artery embolization. Obstet Gynecol 2005; 106: 1165–7. 7. Imbar T, Bloom A, Ushakov F, Yagel S. Uterine artery embolization to control hemorrhage after termination of pregnancy implanted in a cesarean delivery scar. J Ultrasound Med 2003; 22: 1111–5. 8. Ophir E, Singer-Jordan J, Oettinger M, Odeh M, Tendler R, Feldman Y, Fait V, Bornstein J. Uterine artery embolization for management of interstitial twin ectopic pregnancy: case report. Hum Reprod 2004; 19: 1774–7.


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SUPPLEMENTARY MATERIAL ON THE INTERNET The following material is available from the Journal homepage: http://www.interscience.wiley.com/jpages/ 0960–7692 (restricted access) Videoclip S1 Video obtained during laparoscopy showing a protrusion of the ectopic gestational sac with active bleeding. Videoclip S2 Video showing the gestational sac located within the isthmic area of the lower anterior wall of the uterus, protruding towards the vesicouterine junction. The empty uterine cavity, disrupted anterior wall, gestational sac and bladder are marked.

Published online in Wiley InterScience (www.interscience.wiley.com) DOI:10.1002/uog.5289.

