**2. Current opinion and therapeutic strategy on ectopic pregnancies**

Ectopic pregnancy is a complication of pregnancy in which the fetus implants outside the endometrial cavity, which ultimately ends in death of the fetus. It constitutes 1.6% of all pregnancies (Lurie, 1992). Most ectopic pregnancies are located in the fallopian tube, but the implantation can also occur in the cervix, ovaries, abdomen, and even cesarean scars. Ectopic pregnancy is usually not viable. If left untreated, half of ectopic pregnancies will resolve without treatment and presents as the tubal abortions. Ectopic pregnancies are considered as a dangerous health problem for women of childbearing age because of the internal bleeding as a common complication. In fact, maternal mortality is 0.14% in cases of ectopic pregnancy (Lurie, 1992; Te Linde, Rock, & Thompson, 1997).

Within various forms of ectopic pregnancies, cesarean scar pregnancy is a rare form of ectopic implantation. The pathogenesis is thought to be a normal fertilization followed by implantation at the ecchymotic lesion site which is bulging from the uterine wall at the

<sup>\*</sup> Corresponding Author

The Treatment of Ectopic Pregnancy with

Laparoscopy-Assisted Local Injection of Chemotherapeutic Agents 219

pregnancy, and there are still no criteria established. Even in cases of all kinds of ectopic pregnancy, the uses of etoposide were reported in less than ten cases since 1990 (C. L. Chen, Wang, Chiu, Yang, & Hung, 2002; Juan, et al., 2008; Mantalenakis, et al., 1995; Seki, Kuromaki, Takeda, & Kinoshita, 1997; Takashima, et al., 1995). Herein we demonstrated various cases including ovarian, CS scar, and tubal pregnancies successfully treated by laparoscopic local injection of etoposide with trans-vaginal sonography -assisted localization. Furthermore, since etoposide and methotrexate have been applied locally to treat ectopic pregnancy, we evaluated the clinical efficacies of local treatment of these two chemotherapeutic agents.

**3. Cases: The treatment of cesarean scar and ovarian pregnancies with** 

Case I: A 37 year-old-female, gravida 5, para 2 (cesarean section twice), abortion 2, had presented with a 8-week history of gestational amenorrhea. She accidentally found herself pregnancy and asked for an elective abortion in a local clinic. Her general condition was fair. She was considered intra-uterine pregnancy at local clinic and uterine curettage had been performed 3 times since she kept suffering from vaginal bleeding after first curettage. She came to our hospital for second opinion due to persistent vaginal bleeding. trans-vaginal sonography revealed an empty uterus and suggested an ectopic sac of 1.9 × 1.7 cm in diameter between anterior wall of uterus and bladder on previous cesarean scar. β-hCG level was measured at 572.2 mIU/mL. Based on these findings, a cesarean pregnancy was suspected. A laparoscopy was then performed while an ecchymotic lesion (2cm) found bulging from the uterine wall at the previous cesarean scar area. The two fallopian tubes and two ovaries were intact and normal. Confirmed with trans-vaginal sonography, the mass was indicated

Fig. 1. Chemotherapeutic agent was injected into the ectopic sac laparoscopically, followed

by bipolar electrocoagulation (black arrow).

**laparoscopy-assisted local injection of etoposide** 

cesarean scar. If a caesarean scar pregnancy continues developing to second or third trimesters, there might be risks of uterine rupture or catastrophic hemorrhage which may cause serious maternal morbidity and loss of fertility. Differential diagnosis and early diagnosis of such an ectopic pregnancy is now more feasible because of the use of highresolution transvaginal sonography and the availability of sensitive -hCG assay.

Primary ovarian pregnancy is also considered as an uncommon form of ectopic implantation and represents 0.5%–3% of all ectopic pregnancies. The pathogenic mechanism is thought to be fertilization occurring outside the tube, followed by implantation within the ovary. Differential diagnosis of an ovarian pregnancy from a tubal pregnancy has been a challenge in the past. However, due to the improvement of high-resolution transvaginal sonography and the availability of sensitive -hCG assay, an early diagnosis of an ovarian pregnancy is now more feasible.

Once diagnosed, the conventional treatment of ectopic pregnancy is surgical approach. The traditional method for management of a cesarean scar pregnancy is surgical removal of the ectopic pregnancy (Arslan, et al., 2005; C. B. Wang & Tseng, 2006; Y. L. Wang, Su, & Chen, 2006). There have been few reports showing that cesarean scar pregnancies were successfully treated by local injection of methotrexate (Hwu, Hsu, & Yang, 2005; Ravhon, Ben-Chetrit, Rabinowitz, Neuman, & Beller, 1997). Similarly, the traditional management mean for ovarian pregnancy is surgical removal of the ectopic site, either by ipsilateral oophorectomy or wedge resection by laparotomy or laparoscopy(Yen & Wang, 2004). There has been sporadic case reports showing that ovarian pregnancy was successfully treated by systemic methotrexate injection (Chelmow, Gates, & Penzias, 1994; Field & Faraj, 2005; Habbu & Read, 2006).

Methotrexate is not yet a first-line treatment for ovarian pregnancy or cesarean scar pregnancy even in candidates who meet the criteria for medical treatment (Bagga, Suri, Verma, Chopra, & Kalra, 2006; Medical treatment of ectopic pregnancy," 2006). However, the use of systemic methotrexate treatment has considered being an option to preserve potential fertility in ectopic pregnancy patients (Hung, Jeng, Yang, Wang, & Lan, 1996; Marcovici, Rosenzweig, Brill, Khan, & Scommegna, 1994; Timor-Tritsch, et al., 1994). Several risk factors have to be evaluated while systemic methotrexate is indicated for the treatment of ectopic pregnancy. The patient should be hemodynamically stable, have no severe contraindications to methotrexate. Furthermore, the size of the gestation sac should not exceed 3 cm under ultrasound measurement, and the serum β-hCG level should not exceed 2000 mIU/mL. In cases of tubal ectopic pregnancy, the presence of an embryonic cardiac activity was generally considered to be a contraindication to methotrexate therapy (Ory, 1992). Ushakov et al. reported that the side effects of systemic methotrexate treatment occurred 15% of the time, which include bone marrow depression, stomatitis, anorexia, nausea, vomiting, and diarrhea (Floridon & Thomsen, 1994; Ushakov, Elchalal, Aceman, & Schenker, 1997). These contraindications and side effects have become the limitations of systemic treatment of methotrexate on ectopic pregnancy.

AS a result, considering the highly vascularized tissues involved in the surgical procedure and the contraindications of systemic therapy, local injection of the chemotherapeutic agents is then suggested. There have been few reports showing that ectopic pregnancies were successfully treated by local injection of methotrexate or etoposide (C. H. Chen, Wang, & Liu, 2009; Hwu, et al., 2005; Juan, Wang, Chen, Ma, & Liu, 2008; Ravhon, et al., 1997). With laparoscopic local injection, the chemotherapeutic agent such as methotrexate or etoposide could be precisely injected into the ectopic implantation. These procedures lead to a significant decline in side effects and contribute to the preservation of the patients' reproductive potential. However, comparing to methotrexate, etoposide is not yet a widely used treatment for ectopic

cesarean scar. If a caesarean scar pregnancy continues developing to second or third trimesters, there might be risks of uterine rupture or catastrophic hemorrhage which may cause serious maternal morbidity and loss of fertility. Differential diagnosis and early diagnosis of such an ectopic pregnancy is now more feasible because of the use of high-

Primary ovarian pregnancy is also considered as an uncommon form of ectopic implantation and represents 0.5%–3% of all ectopic pregnancies. The pathogenic mechanism is thought to be fertilization occurring outside the tube, followed by implantation within the ovary. Differential diagnosis of an ovarian pregnancy from a tubal pregnancy has been a challenge in the past. However, due to the improvement of high-resolution transvaginal sonography and the availability of sensitive -hCG assay, an early diagnosis of an ovarian

Once diagnosed, the conventional treatment of ectopic pregnancy is surgical approach. The traditional method for management of a cesarean scar pregnancy is surgical removal of the ectopic pregnancy (Arslan, et al., 2005; C. B. Wang & Tseng, 2006; Y. L. Wang, Su, & Chen, 2006). There have been few reports showing that cesarean scar pregnancies were successfully treated by local injection of methotrexate (Hwu, Hsu, & Yang, 2005; Ravhon, Ben-Chetrit, Rabinowitz, Neuman, & Beller, 1997). Similarly, the traditional management mean for ovarian pregnancy is surgical removal of the ectopic site, either by ipsilateral oophorectomy or wedge resection by laparotomy or laparoscopy(Yen & Wang, 2004). There has been sporadic case reports showing that ovarian pregnancy was successfully treated by systemic methotrexate

injection (Chelmow, Gates, & Penzias, 1994; Field & Faraj, 2005; Habbu & Read, 2006).

limitations of systemic treatment of methotrexate on ectopic pregnancy.

Methotrexate is not yet a first-line treatment for ovarian pregnancy or cesarean scar pregnancy even in candidates who meet the criteria for medical treatment (Bagga, Suri, Verma, Chopra, & Kalra, 2006; Medical treatment of ectopic pregnancy," 2006). However, the use of systemic methotrexate treatment has considered being an option to preserve potential fertility in ectopic pregnancy patients (Hung, Jeng, Yang, Wang, & Lan, 1996; Marcovici, Rosenzweig, Brill, Khan, & Scommegna, 1994; Timor-Tritsch, et al., 1994). Several risk factors have to be evaluated while systemic methotrexate is indicated for the treatment of ectopic pregnancy. The patient should be hemodynamically stable, have no severe contraindications to methotrexate. Furthermore, the size of the gestation sac should not exceed 3 cm under ultrasound measurement, and the serum β-hCG level should not exceed 2000 mIU/mL. In cases of tubal ectopic pregnancy, the presence of an embryonic cardiac activity was generally considered to be a contraindication to methotrexate therapy (Ory, 1992). Ushakov et al. reported that the side effects of systemic methotrexate treatment occurred 15% of the time, which include bone marrow depression, stomatitis, anorexia, nausea, vomiting, and diarrhea (Floridon & Thomsen, 1994; Ushakov, Elchalal, Aceman, & Schenker, 1997). These contraindications and side effects have become the

AS a result, considering the highly vascularized tissues involved in the surgical procedure and the contraindications of systemic therapy, local injection of the chemotherapeutic agents is then suggested. There have been few reports showing that ectopic pregnancies were successfully treated by local injection of methotrexate or etoposide (C. H. Chen, Wang, & Liu, 2009; Hwu, et al., 2005; Juan, Wang, Chen, Ma, & Liu, 2008; Ravhon, et al., 1997). With laparoscopic local injection, the chemotherapeutic agent such as methotrexate or etoposide could be precisely injected into the ectopic implantation. These procedures lead to a significant decline in side effects and contribute to the preservation of the patients' reproductive potential. However, comparing to methotrexate, etoposide is not yet a widely used treatment for ectopic

resolution transvaginal sonography and the availability of sensitive -hCG assay.

pregnancy is now more feasible.

pregnancy, and there are still no criteria established. Even in cases of all kinds of ectopic pregnancy, the uses of etoposide were reported in less than ten cases since 1990 (C. L. Chen, Wang, Chiu, Yang, & Hung, 2002; Juan, et al., 2008; Mantalenakis, et al., 1995; Seki, Kuromaki, Takeda, & Kinoshita, 1997; Takashima, et al., 1995). Herein we demonstrated various cases including ovarian, CS scar, and tubal pregnancies successfully treated by laparoscopic local injection of etoposide with trans-vaginal sonography -assisted localization. Furthermore, since etoposide and methotrexate have been applied locally to treat ectopic pregnancy, we evaluated the clinical efficacies of local treatment of these two chemotherapeutic agents.
