**4. Discussion**

102 Ectopic Pregnancy – Modern Diagnosis and Management

Fig. 3. Postoperative declines in serum human chorionic gonadotropin (hCG) levels during the first week after laparoscopic salpingotomy in the successfully treated patients (control group, black line [95% confidence interval]) an PEP patients (Black boxes [individual hCG declines]). Between the black lines is presented 95% confidential interval of the control

Fig. 4. Analysis by receiver operating characteristic curve correlating sensitivity of the test with the false-positive rate (1-specificity) for each postoperative period for the first week following laparoscopic salpingotomy. Sensitivity and specificity were calculated with optimal points in each period, and the excellent sensitivity and false positive rate (1 specificity) were plotted on this figure. A 14% of preoperative serum human chorionic gonadotropin (hCG) value in period C and D revealed that the specificity and sensitivity of

group. Black boxes present individual preoperative hCG values.

the test were equal to 100%.

As indicated by the results of the present study, prophylactic local administration of MTX into the tubal wall immediately after linear salpingostomy is extremely effective in preventing post-operative PEP. In addition, even when systemic MTX administration was effective, patients who developed PEP required a significantly longer follow-up of hCG level than patients without PEP.

MTX has been shown to have no adverse effects on future pregnancies as long as pregnancy is avoided for a certain period of time,15 and may thus be proactively used as prophylaxis following salpingostomy. Graczykowski et al.7 reported that the incidence of PEP was reduced to 1.9% following a single systemic administration of prophylactic MTX (1 mg/kg) within 24 hours after salpingostomy. However, although generally mild, side effects related to systemic MTX administration have been reported in up to 24% of cases,8 including some cases of serious side effects.9 Therefore, the implementation of prophylactic systemic administration of MTX for all patients remains controversial. Importantly, local intratubal administration of MTX has been reported to enhance local anti-trophoblastic activity,16 in addition to reducing side effects,17,18 and may thus be a more effective and safer regimen for preventing PEP. This assumption is supported by the fact that no cases of PEP or side effects were observed in the MTX group in the present study, while PEP was observed in 1.9% of cases in a study involving single systemic administration of MTX.8

Regarding the toxicity to the tube of local administration of MTX (50 mg), no effects were reported in a histologic study of intratubal injection of MTX (100 mg).19 Furthermore, subsequent fertility after local MTX injection was satisfactory.13,20 Therefore, local administration of MTX (50 mg) was thought to have no toxicity in the tube.

Administration of prophylactic MTX to all patients remains a controversial issue. Prophylactic administration of MTX may be appropriate for patients at increased risk for developing PEP, such as patients with a short duration of amenorrhea, a small ectopic pregnancy (< 2 cm in size), and a preoperative hCG level ≥ 2500 IU/ml.21 Considering that no side effects were reported after local MTX administration in the present study, and in light of the risk of salpingectomy and the need for long follow-up in cases of PEP, it may be appropriate to consider prophylactic local administration for all patients.

This study also showed that age, parity, gravity, gestational age, specimen diameter, and preoperative serum hCG levels are not predictive of a PEP following a laparoscopic salpingostomy. Several attempts have been made to predict a PEP; however, no effective predictive protocols for PEP currently exist.22 Because our results were comparable and decreasing pattern of serum hCG has been reported to be helpful aid in avoiding further surgery,23 serum hCG levels must be closely monitored in all patients who have had a salpingostomy before PEP is ruled out.

In the current study, no difference existed in the decline in serum hCG postoperatively between the PEP and control groups during period A; however, after period B, the decline in serum hCG in patients with PEP was significantly less than the control group. This finding indicates that a subsequent increase in the serum hCG level occurs during period B in the PEP group (approximately 3-4 days postoperatively).

Previous studies have used the decline in serum hCG to detect a PEP24-26; however, all of the studies have used a single early post-operative hCG measurement. We indicated that the future course of serum hCG cannot be predicted reliably from a single early postoperative measurement. In our study, during period B, the hCG decline in patients with PEP began to be less than the 95% CI of the control group, and from period C, the decline in PEP group was

Persistent Ectopic Pregnancy After Laparoscopic

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**6. References** 

Linear Salpingostomy for Tubal Pregnancy: Prevention and Early Detection 105

Prophylactic local administration of MTX after laparoscopic salpingostomy may be appropriate for patients at increased risk for PEP20,27-29, specifically patients with a short duration of amenorrhea and a small ectopic pregnancy site. The hCG decline in periods A and B should be compared with period C and if a rise in serum hCG occurs, MTX should be administered. Conversely, if a continuous decline in serum hCG is confirmed and if the serum hCG decline is < 14% in period C, the measurement interval for serum hCG can be

[1] Seifer DB, Diamond MP, Decherny AH: Persistent ectopic pregnancy. Obstet Gynecol

[2] Vermesh M, Silva PD, Rosen GF, et al.: Management of unruptured ectopic gestation by

[3] Murphy AA, Nager CE, Wujek JJ, et al.: Operative laparoscopy versus laparotomy for

[4] Seifer DB, Gutmann JN, Grant WD, et al.: Comparison of persistent ectopic pregnancy

[5] Tanaka T, Hayashi H, Kutsuzawa T, et al.: Treatment of interstitial ectopic pregnanacy with methotrexate: report of a successful case. Fertil Steril 1982;37:851-852. [6] Ory SJ, Villanueva AJ, Sand PK, et al.: Conservative treatment of ectopic pregnancy with

[7] Graczykowski JW, Mishell DR: Methotrexate prophylaxis for persistent ectopic

[8] Parker J, Bisits A, Proietto AM: A systematic review of single-dose intramuscular

[9] Isaacs JD Jr, McGehee RP, Cowan BD: Life-threating neutropenia following methotrexate

[10] Pansky M, Bukovsky I, Golan A, et al.: Local methotrexate injection : a nonsurgical treatment of ectopic pregnancy. Am J Obstet Gynecol 1989;161:393-396. [11] Akira S, Ishihara T, Yamanaka A, et al.: Laparoscopy with ultrasonographic guidance of

[12] Menard A, Crequat J, Mandelbrot L, et al.: Treatment of unruptured tubal pregnancy by

[13] Fernandez H, Benifla J-L, Lelaidier C, et al.: Methotrexate treatment of ectopic

linear salpingotomy: a prospective, randomized clinical trial of laparoscopy versus

the management of ectopic pregnancy: A prospective trial. Fertil Steril

after laparoscopic salpingostomy versus salpingostomy at laparotomy for ectopic

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treatment of ectopic pregnancy: a report of two case. Obstet Gynecol 1996; 88:694-

intraamniotic methotrexate injection for ectopic pregnancy: a report of two cases. J

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completely outside the 95% CI of the control group. In addition, the subsequent increase in hCG was observed after period C in all PEP patients. Furthermore, once an increase in the serum hCG levels was observed, the serum hCG levels never decreased until the second intervention. Therefore, the decision to perform a second intervention, including MTX treatment, should be made by confirming a rise in the hCG levels from period A or B to period C. We also evaluated the appropriate duration of intensive hCG measurement to rule out a PEP. After period C, the hCG decline in all patients with PEP was completely outside the 95% CI of the control group. Furthermore, based on the results of the ROC analysis of the two groups, the specificity and sensitivity were equal to 100% from period C (Figure 4). These results indicate that intensive serum hCG monitoring after laparoscopic salpingostomy must be continued through period C; if the level of the hCG declines to < 14% of the preoperative level, PEP can be ruled out and the serum hCG monitoring interval can be extended.

### **5. Conclusions**

We suggest that prophylactic intratubal injection of MTX after a linear salpingostomy for tubal pregnancy is a safe and effective regimen for preventing PEP, enhances the possibility of tubal preservation, and contributes to improvements in the postoperative QOL of patients.

The decision-making for a second intervention to PEP should be made by confirming an increase of the serum hCG levels from period A or B to period C. Intensive hCG follow-up after laparoscopic salpingostomy for tubal pregnancy must continue through period C; if the serum hCG decline is < 14%, a PEP can be ruled out and the serum hCG monitoring interval can be extended.

In view of these findings, serum hCG follow-up after laparoscopic salpingostomy can be as follows (Figure 5).

Fig. 5. Strategy for management of ectopic pregnancy after laparoscopic salpingotomy. hCG: human chorionic gonadotropin, MTX: methotrexate, PEP: persistent ectopic pregnancy.

Prophylactic local administration of MTX after laparoscopic salpingostomy may be appropriate for patients at increased risk for PEP20,27-29, specifically patients with a short duration of amenorrhea and a small ectopic pregnancy site. The hCG decline in periods A and B should be compared with period C and if a rise in serum hCG occurs, MTX should be administered. Conversely, if a continuous decline in serum hCG is confirmed and if the serum hCG decline is < 14% in period C, the measurement interval for serum hCG can be extended to once every 2 weeks until the level becomes undetectable.
