Ectopic pregnancy, defined as a gestation where the blastocyst implants outside of the uterine cavity, accounts for 1–2% of all pregnancies [1],[2]. Unilateral twin tubal ectopic pregnancy occurs between 1 in 20,000 and 1 in 125,000 for live gestations [3],[4]. The incidence of multi-gestation ectopic pregnancy with other implantation sites is unknown, given its rarity. Risk factors for ectopic implantation include current intrauterine device, underlying tubal pathology, infection, inflammation, endometriosis, and previous ectopic pregnancy [2],[5],[6].

Among all ectopic pregnancies, 2–3% implant in the interstitial region of the fallopian tube [2],[6]. Interstitial ectopic pregnancies (IEPs) are associated with greater morbidity and mortality, due to the adjacent vascular anastomosis of the uterine and ovarian arteries and greater myometrial distensibility leading to delayed presentations [7],[8]. For these reasons, IEPs have a 2.5% mortality rate, seven times that of ectopic pregnancies overall [7],[9],[10].

Management approach for ectopic pregnancy depends on several factors, including patient characteristics and stability, initial β-human chorionic gonadotropin (β-hCG) levels, and ultrasound findings. There is no consensus for multi-gestation ectopic pregnancies. Given the lack of clear guidelines and the rarity of these implantations, we report a case of a twin ectopic pregnancy with simultaneous interstitial and tubal implantations in a hemodynamically stable patient, who was successfully treated with systemic multidose methotrexate regimen. We also describe a range of management strategies reported in the literature for twin ectopic pregnancies.

A 31-year-old, gravida 2, para 0, abortus 1 female presented to an early pregnancy assessment clinic (EPAC) at 6+1 weeks gestational age by last menstrual period with a one-week history of vaginal spotting and mild lower pelvic pain. This pregnancy was a spontaneous conception. Her obstetrical history was significant for an expectantly managed first-trimester spontaneous abortion. She was otherwise healthy with no previous surgeries. Two days prior to her presentation, hemoglobin and β-hCG in the community were 13.6 g/dL and 1436 mIU/mL, respectively. At EPAC, her hemoglobin and β-hCG were 13.8 g/dL and 2303 mIU/mL, respectively. An ultrasound demonstrated a left echogenic adnexal mass with peripheral vascularity measuring 16×13 mm with a thickened, heterogeneous endometrium measuring 13 mm, and a moderate amount of free fluid in the cul-de-sac suggestive of hemoperitoneum. Due to the high suspicion for an ectopic pregnancy, she was transferred to our tertiary care hospital.

At our hospital, she continued to have minimal vaginal spotting, but her pain resolved. Her vital signs were stable. Her abdomen was soft and non-tender. A repeat ultrasound similarly demonstrated a 20 mm thickened endometrium with no gestational sac, and a 17×15 mm left adnexal mass with echogenic rind and peripheral vascularity (Figure 1). However, an additional 8×7×5 mm cystic lesion with an echogenic rind and peripheral vascularity was noted at the left cornua with the overlying myometrium measuring 3 mm (Figure 2). No interstitial line sign and no fetal heart rate were noted. There was a small amount of free fluid in the cul-de-sac and left adnexa with low-level internal echoes.

Upon review with radiology, the consensus diagnosis was a twin ectopic pregnancy with implantations in both the left interstitial region and the left fallopian tube. There was no concurrent viable intrauterine pregnancy. The patient was admitted for multidose methotrexate (intramuscular 1 mg/kg) on days 1, 3, 5, and 7, and leucovorin (intramuscular 0.1 mg/kg) on days 2, 4, 6, 8. This is our institution’s standard protocol for managing interstitial pregnancies, and is consistent with current society recommendations. During admission, she remained hemodynamically stable with minimal vaginal bleeding and abdominal pain. Her β-hCG peaked at 3213 mIU/mL on day 5 but subsequently dropped to 2187 mIU/mL by day 9 (Table 1).

A repeat ultrasound on day 7 continued to show a left tubal ectopic pregnancy measuring 26×20×16 mm and a left cornual pregnancy measuring 9×7×6 mm with no free fluid. Given the drop in β-hCG and clinical stability, she was discharged on day 9 with weekly outpatient β-hCG surveillance.

The patient required two additional outpatient investigations outside of our standard protocol. On treatment day 17, she developed mild abdominal pain and light vaginal bleeding, prompting an ultrasound which demonstrated the left tubal pregnancy measuring 3734×30 mm and the interstitial ectopic measuring 9×9×7 mm with a small amount of simple fluid. Her β-hCG level was 949 mIU/mL. Given her stability and decreasing β-hCG, she was expectantly managed. On treatment day 19, her β-hCG level increased to 1316 mIU/mL. However, the β-hCG decreased to 882 mIU/mL when repeated on the same day, and she remained asymptomatic. On day 42, her β-hCG levels were undetectable and she was discharged from care.

Following this twin ectopic pregnancy, the patient subsequently had one spontaneous abortion and a vacuum-assisted vaginal delivery two years later.

Our case demonstrates the successful treatment of a stable patient with a twin interstitial and tubal ectopic pregnancy using systemic multidose methotrexate. As twin ectopic pregnancy is a rare diagnosis, there is no consensus for management. We applied the multidose protocol for singleton IEP, given that one of the gestations was interstitial. This decision was made with consideration of this patient’s hemodynamic stability, lack of signs for rupture, low initial β-hCG, desire to avoid surgical management, and sonographic features of twin ectopic gestations.

To our knowledge, there are no published cases of twin ectopic pregnancies with unilateral tubal and interstitial implantations, in the absence of an intrauterine gestation. We reviewed the literature for twin ectopic pregnancies with other patterns of implantation, including twin tubal ectopic pregnancies and twin IEPs. Management strategies for these included medical management with methotrexate, combined medical and surgical treatment, or surgical alone.

The most similar case includes a tubal and interstitial ectopic pregnancy—but with a concurrent intrauterine twin pregnancy. Given the wanted intrauterine pregnancies, systemic medical management with methotrexate was unacceptable, so the interstitial gestation was treated by ultrasound-guided KCl injection, and the tubal pregnancy was managed with laparoscopic salpingectomy [11].

While twin tubal ectopic pregnancies have been successfully medically managed, significant variation exists in both dosing and scheduling of methotrexate. Fernandez et al. reported a case of a unilateral twin tubal ectopic pregnancy treated with methotrexate, with an initial β-hCG of 3640 mIU/mL [12]. Their regimen consisted of an ultrasound-guided methotrexate injection into each gestational sac, and a dose of intramuscular methotrexate 48 hours later. Meanwhile, Karadeniz et al. reported a case of a unilateral twin tubal ectopic with an initial β-hCG of 987 mIU/mL that was successfully treated with systemic multidose methotrexate, with an additional dose of methotrexate (1 mg/kg) on day 14, as β-hCG reached 1200 IU/mL [13]. Another case of a 7-week twin tubal ectopic pregnancy with an initial β-hCG of 18,780 mIU/mL was successfully treated with a single-dose of 1 mg/kg methotrexate intramuscularly [14].

Successful medical treatment of a twin IEP was first described by Karsdorp et al. (1992) in a case with a pre-treatment β-hCG level of 4400 mIU/mL, using three doses of systemic methotrexate and leucovorin to a cumulative amount of 900 mg of methotrexate [15].

Methotrexate has also shown to be effective for treating twin IEPs when given both locally into the gestational sacs and systemically as a single dose [16].

Several cases have also been reported where medical management failed and subsequent surgical intervention was required. A twin tubal ectopic with an initial β-hCG of 13,217 mIU/mL was initially treated with systemic methotrexate (50 mg/m²) and folinic acid rescue (three doses given on days 1, 7, and 14), but subsequently required emergent laparoscopic salpingectomy due to tubal rupture [17]. In a twin IEP with an initial β-hCG of 15,022 mIU/mL, one embryo remained viable after four courses of methotrexate/leucovorin, requiring an additional 50 mg of methotrexate intramurally during laparoscopy and four additional doses intramuscularly postoperatively [18]. Other therapeutic approaches for twin IEPs included uterine artery embolization after failing systemic multidose methotrexate (initial β-hCG levels 33,689 and 49,997 mIU/mL, respectively) [19],[20], and salpingectomy and resection of the interstitial section after failing multidose methotrexate (initial β-hCG level 60,348 mIU/mL) [21]. A commonality of these failed medical treatments is higher pre-treatment β-hCG level.

Finally, surgical-only treatment of twin IEP with cornual wedge resection, laparoscopic automatic stapler, and conical exeresis of the cornual section have been reported [22],[23],[24]. Surgical management was more common when there was fetal cardiac activity. In 2021, Martin et al. reported a case of a live twin tubal ectopic pregnancy treated by laparoscopic salpingectomy due to fetal cardiac activity [25]. They further identified 21 cases in the literature of live twin ectopic pregnancies, all managed surgically or with a combination of medical and surgical treatment.

Given the study design, this case report has limited generalizability to the general population. The findings and regimen here may not be applicable to other types of twin ectopic implantation locations and patient populations, and careful patient selection is warranted.

In conclusion, we demonstrate successful application of the systemic multidose methotrexate treatment protocol to a unique implantation of twin ectopic pregnancy. We conclude that the multidose methotrexate regimen is a suitable option for patients presenting with similar twin ectopic pregnancies and may be considered when one gestation is interstitial. We suggest consideration of this protocol for patients with twin ectopic pregnancies without a concurrent viable intrauterine pregnancy, who are hemodynamically stable, have a low pre-treatment β-hCG without contraindications to methotrexate, and who are compliant with follow-up. The applicability of this protocol to twin ectopic pregnancies with other implantation sites, higher initial β-hCG levels, or presence of cardiac activity requires further research.