**1. Introduction**

96 Ectopic Pregnancy – Modern Diagnosis and Management

Thorburn, J.; Berntsson, C.; Philipsson, M.; Lindblom, B. (1986). Background factors for

Tuomovaara, L. & Kauppila, A. (1988), Ectopic pregnancy: a case-control study of

Verhulst, G.; Camus, M.; Bollen, N.; Van Steiterghem, A.; Devroey, P. (1993). Analysis of risk

Winston, R.M. & Margara, R.A. (1991). Microsurgical salpingostomy is not an obsolete

Yao, M. & Tulandi, T. (1997). Current status of surgical and non-surgical treatment of

aetiological risk factors. *Arch Gynecol Obstet,* Vol. 243, pp. 5-11.

*Gynecol Reprod Biol,* Vol. 23, pp. 321-331.

procedure. *BJOG* Vol. 98, pp. 637-642.

reproduction. *Hum Reprod,* Vol. 8, pp. 1284-1287.

ectopic pregnancy. *Fertil Steril,* Vol. 67, pp. 421–433.

ectopic pregnancy. Frequency distribution in a case-control study. *Eur J Obstet* 

factors with regard to the occurrence of ectopic pregnancy after medically assisted

Persistent ectopic pregnancy (PEP) is a condition that occurs due to incomplete removal of trophoblastic tissue during fallopian tube-preservation surgery for tubal pregnancy. According to several studies, the incidence has been reported to be approximately 3%-20%,1 and the incidence appears to be rising due to the increase in treatment of tubal pregnancies via laparoscopic surgery.2-4 If treatment for PEP is delayed, tubal rupture and intraabdominal hemorrhage can occur and may be accompanied by significant morbidity and mortality. Therefore, prevention and early detection of PEP is of great importance.

Methotrexate (MTX), a cytostatic agent with proven anti-trophoblastic activity, has been used for the treatment of ectopic pregnancies, and has also been reported to be useful for treating PEPs.5-6 Therefore, combined use of MTX following conservative tubal surgery may facilitate prevention of PEP.

Indeed, MTX has thus far been reported to significantly decrease the occurrence of PEP when systemically-administered in a single dose within 24 hours after laparoscopic linear salpingostomy.7 However, systemic MTX administration has been reported to cause side effects and must be used with caution.8,9 In contrast, local MTX administration into the tube, either laparoscopically10,11 or through transvaginal ultrasonography12,13, has been associated with few side effects, and may be useful as a prophylactic for PEP. Therefore, local MTX administration after linear salpingostomy could prevent PEP without serious side effects.

In this chapter, we examined the efficacy of local MTX administration after linear salpingostomy for tubal pregnancies in preventing PEP, and evaluated the usefulness of postoperative serum human chorionic gonadotropin (hCG) decline (percentage of the preoperative hCG level) for early detection and ruling out of PEP.

## **2. Subjects and methods**

#### **2.1 Patients selection**

Patients who underwent linear salpingostomies between January 1996 and December 2010 were enrolled in the study. A linear salpingostomy was indicated according to the following criteria: 1) stable circulatory dynamics; 2) desired future pregnancy; 3) no tubal rupture; 4) absence of marked tubal adhesions; 5) ectopic pregnancy diameter < 5 cm; 6) absence of a

Persistent Ectopic Pregnancy After Laparoscopic

**3. Results** 

**3.1 Prevention of PEP** 

51.7±17.2 days (p<0.05; Table 2).

**3.2 Early detection of PEP** 

Linear Salpingostomy for Tubal Pregnancy: Prevention and Early Detection 99

A cut-off value for serum hCG to rule out a PEP was established using receiver operating characteristic (ROC) curve analysis. The two groups were compared using the Student's t-test, and when appropriate, Fisher's exact test was used. Significance was defined as a P < 0.05.

One hundred two patients were enrolled in the present study. The prophylaxis and control groups consisted of 55 and 47 patients, respectively, with no intergroup differences in age, gestational age, or preoperative hCG levels. PEP were not noted in the prophylaxis group,

The 8 patients in the control group who developed PEP received a single systemic administration of MTX (50 mg/m2) between postoperative days 7 and 10, the period during which the diagnosis was made. One patient had a poor decline in serum hCG and required an additional administration of MTX (50 mg/m2) 7 days later. In addition, another patient developed lower abdominal pain and a hemoperitoneum 4 days after MTX administration, and underwent laparoscopic salpingectomy. The remaining six patients had a steady decline in serum hCG levels. Patients in both groups who did not develop PEP reached undetectable serum hCG levels, and thus completed the recommended follow-up by postoperative day 28. In contrast, patients who developed PEP required a mean follow-up of

No side effects attributable to MTX, such as dermatitis, alopecia, dyspepsia, and hepatic or

In 42 of the 53 patients, no postoperative symptoms of PEP were noted, and the serum hCG levels dropped to pre-pregnancy levels; the PEP was located in 11 patients. Table 3 presents the clinical characteristics of both groups. No statistically significant differences existed between the PEP and control groups with respect to age, parity, gravidity, gestational age,

Table 1. Patient characteristics and frequency of persistent ectopic pregnancy.

but occurred in 8 patients (17.0%) in the control group (p<0.05; Table 1).

bone marrow toxicity, were observed in the prophylaxis group.

specimen diameter, or preoperative serum hCG levels.

fetal heart beat; and 7) absence of a recurrent ectopic pregnancy in the ipsilateral fallopian tube. For patient selection, we did not limit the gestational age or pre-operative serum hCG level.

#### **2.2 Surgical procedure**

Following confirmation of indication criteria for laparoscopy, 5 IU of vasopressin was injected into the mesosalpinx. After making a linear incision on the distended portion of the fallopian tube with electrocautery, the products of conception were removed *en bloc* using forceps or by hydrodissection. Trophoblasts were macroscopically confirmed in water and sent for pathologic evaluation. The diagnosis of ectopic pregnancy was pathologicallyconfirmed in all cases. Surgery was performed using an identical technique by several physicians under the guidance of a supervising physician.

#### **2.3 Serum hCG measurement**

Preoperative serum hCG levels were obtained < 24 hours before surgery. Serum hCG levels during the first postoperative week were measured at 2-3 day intervals. The intervals between hCG measurements were determined by the attending physician based on clinical symptoms. Serum hCG levels were followed postoperatively until serum hCG levels < 5 IU/ml or until the diagnosis of PEP.

Serum hCG levels were determined by an electrochemiluminescence immunoassay (ECLIA), which is based on a sandwich antibody principle (Elecsys 2010 Systems; Roche Tokyo, Japan). The inter-assay coefficient of variation was 5.8; the intra-assay coefficient of variation was 4.5.

#### **2.4 Prevention of PEP**

Patients were divided into two groups (prophylaxis and control groups). In the prophylaxis group, MTX (50 mg) was serially administered into the tubal wall near the lesion immediately after linear salpingostomy. Patients who underwent surgery without MTX administration were assigned to the control group. All patients gave informed consent to the procedures, and this study was approved by the Nippon Medical School Hospital Ethics Committee.

PEP was defined as an increase in the serum hCG level or a decline of < 20% between measurements taken 3 days apart.14

The incidence of PEP between groups was analyzed using Fischer's exact test. In addition, statistical analysis for both groups used the Student's t-test or the Mann-Whitney test, as appropriate (STATMATE for Windows). Significance was defined as a P < 0.05.

#### **2.5 Early detection of PEP**

The 53 patients without prophylactic MTX injection were divided into two groups, as follows: patients with an increase in the serum hCG level or a decline in the serum hCG level < 20% between measurements taken 3 days apart (PEP group); and successfullytreated patients with a marked decrease in hCG (control group). The clinical and laboratory characteristics of both groups were compared with respect to maternal age, parity, gestational age at enrollment, specimen diameter, and pre-operative serum hCG levels.

The postoperative course was divided into 4 periods, as follows: period A, days 1–2; period B, days 3–4; period C, days 5–6; and period D, days 7–8. The serum hCG declines during each period in the PEP and control groups were compared.

A cut-off value for serum hCG to rule out a PEP was established using receiver operating characteristic (ROC) curve analysis. The two groups were compared using the Student's t-test, and when appropriate, Fisher's exact test was used. Significance was defined as a P < 0.05.
