**7. Conclusion**

200 Ectopic Pregnancy – Modern Diagnosis and Management

The fertility outcome of patients with unruptured EP treated conservatively with either MTX or expectant management can be evaluated indirectly through the hysterosalpingography (HSG) and directly by means of future pregnancy (Debby et al., 2000; Elito et al., 2006). The HSG represents important diagnosis methods after the treatment of EP, in spite of the inconveniences and doubts about the interpretation of this examination. The tubal patency after MTX is 84% and after expectant management is 78% (Elito et al., 2005a). This high rate of radiologically normal tubes after clinical treatment proves that the spontaneous regression of EP does not result in an increased harm or damage to the tube. However, the radiologically normal findings show nothing about the tubal function, when a disturbance can also be the cause of EP. On the other hand, if the results of HSG demonstrate obstruction of the tubes, the possibility of a spontaneous pregnancy will be reduced and should be treated with *in vitro* fertilization. The tubal obstruction is increased in cases with high beta-hCG levels (Elito et al., 2005b). The explanation for higher incidence of tubal obstruction is that in patients with higher levels of beta-hCG there is more invasion

of the trophoblast tissue at the tube's serosa, what increases the damage to the tube.

After medical treatment 65% of patients who attempted subsequent pregnancies succeeded, and the incidence of recurrent ectopic pregnancy was relatively low at 13% (Stovall et al., 1989; Lipscomb et al., 2000). Systemic MTX in a single-dose regimen compared with laparoscopic salpingostomy of four trials (Fernandez et al., 1998; Saraj et al., 1998; Sowter et al., 2001; El-Sherbiny et al., 2003), involving 265 haemodynamically stable women with a small unruptured tubal EP, showed no significant differences in the number of IUPs (RR 1.01, 95% CI 0.66–1.54), whereas there was a non-significant trend towards a lower incidence of repeat EPs (RR 0.63, 95% CI 0.14–2.77) (Mol et al., 2008). Systemic MTX in a fixed multiple dose regimen compared with laparoscopic salpingostomy observed that fertility outcome was no significant different for IUP (RR 0.88, 95% CI 0.49–1.60) as well as for repeat EP (RR

Serial serum beta-hCG measurements and transvaginal ultrasound examination can provide early diagnosis of most ectopic pregnancies allowing medical treatment with methotrexate. Approximately 40% of women diagnosed with ectopic pregnancy are candidates for medical management (Barnhart et al., 2003), and 90% of those can be treated successfully without surgery (Lipscomb et al., 2000). Whereas the costs of surgery and outpatient medical management vary widely, many cost-effectiveness analyses have favored MTX therapy. Systemic MTX in a single-dose regimen resulted in significant savings in direct costs compared with laparoscopic surgery: mean direct costs per patient were € 756 and € 1585, respectively, with a mean difference of € 829 (95% CI 599–1060). Furthermore, systemic MTX resulted in significant savings in indirect costs: mean indirect costs per patient were € 587 and € 977, respectively, with a mean difference of € 390 (95% CI 142–638). However, in women with initial serum hCG concentrations >1500 IU/l the difference in indirect costs was lost due to the prolonged follow-up and a higher rate of surgical re-interventions

**5. Reproductive future 5.1 Hysterosalpingography** 

**5.2 Future pregnancy** 

**6. Cost analysis** 

0.88, 95% CI 0.21–3.67) (Dias Pereira et al., 1999).

The early non-invasive diagnosis of ectopic pregnancy, before there is tubal rupture, can be made through transvaginal ultrasonography and with the dosage of the beta-fraction of the chorionic gonadotrophin. After the diagnosis, range of treatments may be used. Either a surgical intervention or a clinical treatment (expectant management or methotrexate therapy) may be taken into consideration. Expectant management should be indicated in cases of decline in the beta-hCG titers within 48 hours before the treatment, and when the initial titers are under 1,500 mUI/mL. The use of methotrexate (MTX) is a safe clinical procedure and in some cases could be indicated as the first option for treatment. The main criteria for MTX indication are hemodynamic stability, beta-hCG <5,000 mUI/mL, adnexal mass <3,5 cm, and no embryonic cardiac activity. It is preferable to administer a single intramuscular dose MTX (50 mg/m2) because it is easier, more practical and with less side effects (diagram 1). Protocol with multiple doses should be restricted for the cases with atypical localization (interstitial, cervical, caesarean section scar and ovarian) with values of beta-hCG >5,000 mUI/mL and no fetal heart activity. Indication for local treatment with an injection of MTX (1 mg/kg) and KCl guided by transvaginal ultrasonography should occur in cases of embryonic cardiac activity but with an atypical localization (Elito et al., 2008).

Diagram 1. Recommendation for Treatment of Unruptured Tubal Pregnancy (Elito et al., 2008)

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**12** 

*Japan* 

1Yoshiki Yamashita et al.\*

**MTX Could Be First-Line Therapy Even in Cases** 

Ectopic pregnancy (EP) accounts for approximately 75% of deaths in the first trimester, and

Recently, EP can be diagnosed accurately at a very early stage using transvaginal ultrasound and serum hCG measurement (1). Methtorexate (MTX) is in a class of drugs known as folic acid antagonists, and folic acid is an essential component in the synthesis of DNA precursors such as purines and thymidylate. MTX was originally used to treat cancer, trophoblastic disease, psoriasis, and rheumatoid arthritis; however, since 1982, it has been used to successfully treat EP (2). Treatment with MTX now reportedly achieves results comparable to surgery for the treatment of appropriately selected ectopic pregnancies and is now commonly used (3). The American Society of Reproductive Medicine (ASRM) introduced the relative and absolute contraindications to MTX therapy, as indicated in Table 1 and 2 (4, 5). Lipscomb et al reported that the rate of success with MTX is relatively low in cases where serum hCG levels are higher than 5,000 IU/ml (Table 3) (6), however, MTX treatment has recently been favored in cost-effectiveness analyses. In this study, we reviewed EP cases treated with MTX regardless of high initial-hCG levels (>5,000 IU/ml) and evaluated the effectiveness of MTX by comparing them with cases where hCG levels

1. Embryonic cardiac activity detected by transvaginal ultrasonography

2. High initial hCG concentration (5,000>mIU/ml)

\*Sousuke Katoh, Yoko Yoshida, Satoe Fujiwara, Sachiko Kawabe, Mika Hayashi,

3. Ectopic pregnancy >4 cm in size as imaged by transvaginal

9% of all pregnancy-related deaths are the result of EP.

**1. Introduction** 

were less than 5,000 IU/ml.

ultrasonography

Table 1. Relative contraindication to MTX

Atsushi Hayashi, Yoshito Terai and Masahide Ohmichi

4. Refusal to accept blood transfusion 5. Inability to participate in follow-up

**Where hCG Level is Greater than 5,000 IU/ml** 

*Department of Obstetrics and Gynecology, Osaka Medical College* 

