Local Methotrexate Plus Uterine Artery Embolization for High-Risk Interstitial Ectopic Pregnancy

Abstract

Interstitial ectopic pregnancy involves the interstitial portion of the fallopian tube and is among the most hazardous of all ectopic pregnancies, with the highest risk of uterine rupture and maternal mortality. Unlike tubal ectopic pregnancy, management of interstitial pregnancy is not well standardized. Systemic methotrexate (MTX) and surgical resection are the primary treatment options; however, failure rates and risk of bleeding remain high. Alternative minimally invasive techniques have been described—including uterine artery embolization (UAE) and local injection of MTX or potassium chloride—and may confer improved success rates. We report a case of a high-risk 28-year-old female with an interstitial ectopic pregnancy successfully treated with combined local injection of MTX plus UAE. We describe our technique and the unique medical management in the setting of a known bleeding disorder.

Ectopic pregnancy results when the embryo implants outside of the endometrium of the uterus and can potentially be a life-threatening condition. Hemorrhage from ectopic pregnancy remains the leading cause of pregnancy-related maternal mortality in the first trimester; therefore, early detection and appropriate management are paramount. ¹ Most ectopic pregnancies occur in the fallopian tube; however, other less common sites include cervical, interstitial, hysterotomy or cesarean scar, intramural, ovarian, or abdominal.

Interstitial ectopic pregnancy (historically described as cornual pregnancy) involves the interstitial portion of the fallopian tube, defined as the proximal segment embedded within the muscular wall of the uterus. Although uncommon, accounting for only 2 to 4% of all ectopic pregnancies, interstitial pregnancies can be misdiagnosed as intrauterine because they are partially implanted in the endometrium. However, interstitial ectopic pregnancies are considered the most hazardous of all ectopic pregnancies, with uterine rupture occurring in approximately 20% of cases beyond 12 weeks of gestation. ^{2 3}

With early diagnosis, most ectopic pregnancies can be treated medically with methotrexate (MTX), while the remainder of patients require or may prefer surgical management. When medical management is desired, tubal ectopic pregnancies are typically safely treated with a single or two-dose MTX protocol. ⁴ Interstitial ectopic pregnancies can also be treated with systemic MTX and require multi-dose protocols; however, failure rates up to 20% have been reported. ² More recently, reasonable alternatives have been described—including selective uterine artery embolization (UAE), local injection of MTX, or local injection of potassium chloride (KCl), with or without systemic MTX—and may confer improved success rates. ^{5 6 7 8} However, to date, only limited case reports and case series exist in the literature describing UAE with or without systemic or local MTX as a treatment option for complex or high-risk ectopic pregnancies.

The authors present a case of a 28-year-old woman with an interstitial ectopic pregnancy successfully treated with combined local injection of MTX plus UAE. The authors describe technique as well as the unique medical management in the setting of a known qualitative platelet aggregation disorder.

Case Presentation

A 28-year-old woman G1P0 with a past medical history of a qualitative platelet aggregation disorder initially presented to the emergency department (ED) at approximately 6 weeks, 1 day of gestation with abdominal pain. Beta-human chorionic gonadotropin (β-hCG) was 5,406 mIU/mL and transvaginal ultrasound (TVUS) demonstrated a gestational sac located in the right cornua of the uterus with fetal cardiac activity compatible with an interstitial ectopic pregnancy ( Fig. 1 ). The patient was subsequently discharged from the ED against medical advice (AMA). She represented 5 days later with vaginal bleeding, β-hCG of 13,346 mIU/mL, and TVUS redemonstrating a live interstitial ectopic pregnancy ( Fig. 2 ). She again declined treatment and left AMA. She finally presented again at approximately 7 weeks of gestation with persistent vaginal bleeding and dizziness, unchanged TVUS, and β-hCG of 18,989 mIU/mL. She was admitted to the obstetrics and gynecology service with consult to interventional radiology and hematology.

Fig. 1.

Transverse and sagittal gray scale ultrasound images demonstrate a 2.4-cm gestational sac (arrow) containing a fetal pole (star) with cardiac activity (not shown) located in the interstitial area of the right uterus compatible with a live interstitial ectopic pregnancy.

Fig. 2.

Three-dimensional ultrasound image demonstrating thickened endometrium (star) and the interstitial “line sign” (curved arrow), highly sensitive and specific for interstitial ectopic pregnancy (straight arrow).

Following extensive multidisciplinary discussion, the patient elected to proceed with local MTX plus UAE and concurrent multidose systemic MTX. Systemic MTX regimen included MTX 1 mg/kg IM on hospital days 1, 3, 5, and 7, alternating with folinic acid 0.1 mg/kg IV on hospital days 2, 4, 6, and 8.

Due to her history of platelet aggregation disorder, a protocol of desmopressin (DDAVP) and aminocaproic acid (Amicar; Akorn, Lake Forest, IL) was administered to decrease bleeding risk peri- and postprocedurally. She received DDAVP 0.3 μg/kg IV and aminocaproic acid 2 g IV 30 minutes preprocedure, followed by aminocaproic acid 2 g every 6 hours for a total 7-day course postprocedure.

At a gestational age of approximately 7 weeks and 5 days, she was taken to the interventional radiology suite under moderate sedation. The patient received cefazolin 1 g IV prior to the procedure. Local injection of MTX was performed by obstetrics and gynecology under direct ultrasound guidance via a percutaneous transabdominal approach ( Fig. 3 ). A 22-gauge needle was advanced into the interstitial gestational sac with subsequent delivery of 2 mL (50 mg) of MTX; 1 mL was directed intraembryonic and 1 mL was delivered into the placental/chorionic bed.

Fig. 3.

Gray scale ultrasound image localization of the interstitial ectopic pregnancy (arrow) prior to percutaneous transabdominal intrasac injection of methotrexate.

Uterine artery embolization was then performed via contralateral left common femoral artery access with a 5-Fr sheath. The left radial artery was too small, precluding radial access. A 5-Fr Cobra 2 catheter (Merit, South Jordan, UT) was used to select the right uterine artery and digital subtraction angiogram demonstrated a dilated, tortuous uterine artery with a rounded intensely vascular focus within the right uterus compatible with known interstitial ectopic pregnancy ( Fig. 4a ). Embolization of the right uterine artery was performed with Gelfoam slurry until stasis ( Fig. 4b ). The 5-Fr Cobra catheter was exchanged for a 5-Fr Roberts uterine catheter (RUC; Cook, Bloomington, IN), and used to select the ipsilateral left uterine artery. Digital subtraction angiogram demonstrated a dilated, tortuous left uterine artery ( Fig. 4c ), and embolization was performed with Gelfoam slurry until stasis ( Fig. 4d ). Cumulative radiation dose was 33.5 mGy.

Fig. 4.

Digital subtraction angiogram images demonstrate a dilated and tortuous right uterine artery (curved arrow) with a rounded, intensely vascular focus (straight arrow) in the right uterus compatible with known interstitial ectopic pregnancy ( a ), and postembolization stasis in the right uterine artery ( b ). A dilated and tortuous left uterine artery (arrow) ( c ) and post-embolization stasis ( d ).

The postprocedure course was uncomplicated. The patient's β-hCG rapidly declined over the next several days ( Fig. 5 ). She experienced no significant bleeding and only expected post-UAE pelvic pain. She was discharged home on postoperative day 4 in good condition with close outpatient follow-up, continued downtrend in β-hCG, and successful resolution of the ectopic pregnancy.

Fig. 5.

Plot graph demonstrates β-hCG (mIU/mL) levels over time with rapid decline in β-hCG following uterine artery embolization (UAE) + local methotrexate (MTX) procedure. By postoperative day 4 (POD # 4), the β-hCG was less than half of the peak.

Discussion

Although a rare form of ectopic pregnancy, interstitial pregnancy carries maternal mortality rates as high as 2 to 3%, significantly higher than other ectopic pregnancies. ⁹ However, detection of interstitial pregnancy can be challenging and may be misdiagnosed as intrauterine. ² There are several sonographic signs to aid in diagnosis of interstitial pregnancy, including eccentric location of the gestational sac proximal to the uterine cornua, the “interstitial line sign,” myometrium incompletely surrounding the sac (<5 mm myometrial thickness around the chorionic sac), and a chorionic sac located separately from the lateral edge of the uterine cavity. Of these, the interstitial line sign—defined as an echogenic line extending from the superior and lateral portion of the endometrium to the mid portion of the gestational sac ( Fig. 2 )—is suggested to be more useful than other sonographic findings, with reported sensitivity of 80% and specificity of 98%. ¹⁰

Management of interstitial ectopic pregnancy is not standardized. Surgical treatment options include ectopic resection via laparotomy, laparoscopic, or hysteroscopic approaches. However, surgical management is particularly high risk for hemorrhage due to the rich vascular supply of the interstitial area, near the anastomosis of the uterine and ovarian vessels. The anatomy also increases the risk of subfertility following treatment. Medical management typically involves multiple-dose systemic MTX regimens administered intramuscularly or intravenously and subsequent surveillance until β-hCG levels are undetectable, with variable rates of success. ^{2 11}

Interstitial ectopic pregnancies managed with UAE and local injection of MTX or KCl, with or without systemic MTX, have also been described. In one retrospective study of 38 patients with interstitial pregnancy, those treated with local MTX had higher rates of pregnancy resolution compared to those treated with systemic MTX (87.5 vs. 46.7%, respectively). ⁸ Others have reported successful treatment of interstitial ectopic pregnancy by selective UAE without any serious complications. ^{6 7 9} Blocking blood flow within the highly vascular region of the uterine interstitial area decreases vascularization of the pregnancy leading to trophoblastic degeneration and subsequent pregnancy resolution.

Combination UAE with administration of MTX has also been described in case reports for the treatment of interstitial ectopic pregnancy, as well as other rare ectopic pregnancies, with excellent clinical outcomes. ^{12 13 14 15} Tamarit et al described three cases of interstitial ectopic pregnancy treated with UAE and local injection of MTX. These cases were considered high-risk and of poor prognosis due to high β-hCG and failed systemic MTX. All three cases resulted in successful resolution of the pregnancy. ¹² In a different series of eight patients, Hirakawa et al evaluated the technical and clinical outcomes of UAE along with MTX for cervical ectopic pregnancies. All patients were treated with UAE and seven of eight patients were also treated with MTX (two local injections and five systemic). Technical success rate was 100%, with clinical success of 75%; two patients required repeat UAE. The uterus was preserved in all patients. Additionally, three patients with long-term follow-up all had subsequent successful pregnancies. ¹⁵ Preserved fertility is consistent with the other reports in the literature documenting successful pregnancies following UAE for ectopic pregnancy, postpartum hemorrhage, and arteriovenous malformations. ^{6 9 16 17}

This case adds to the growing literature to support the use of UAE in combination with local MTX for successful resolution of interstitial ectopic pregnancy. A unique challenge important to this case was the patient's history of platelet aggregation disorder, placing her at particularly high risk for bleeding. Therefore, careful consideration was made to mitigate bleeding risk peri- and postprocedurally. The patient had previously tolerated a tonsillectomy with the use of DDAVP and antifibrinolytic agents. Per the recommendations of hematology, a similar protocol was adopted for the treatment of the interstitial ectopic pregnancy. DDAVP is a synthetic analog of the antidiuretic hormone arginine vasopressin, which, in addition to its antidiuretic effects, also increases plasma levels of von Willebrand factor, factor VIII, and t-PA, promoting a decreased activated partial thromboplastin time and bleeding time. Aminocaproic acid (Amicar) is an antifibrinolytic agent that competitively binds to plasminogen thereby inhibiting the degradation of fibrin. Together these agents help promote intrinsic clotting mechanisms and decrease bleeding risk.

The patient's postprocedural course was uneventful. Her β-hCG rapidly declined over the next 4 days to less than half of its peak. With close outpatient follow-up, the β-hCG continued to downtrend steadily. She experienced no significant bleeding and ultimate resolution of the ectopic pregnancy. This case further demonstrates that UAE along with MTX administration offers an effective and safe treatment option for the management of interstitial ectopic pregnancy, and may be particularly useful in patients with increased bleeding risk. Ultimately, more data are necessary to standardize the optimal treatment algorithm. This case also emphasizes the importance of a collaborative multidisciplinary approach involving obstetrics and gynecology, interventional radiology, and hematology to provide effective clinical outcomes and minimize risk in these complex patient populations.