**1. Introduction**

208 Ectopic Pregnancy – Modern Diagnosis and Management

Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto S, Ichinoe K. Treatment of intersticial ectopic

Tawfiq A, Agameya AF, Claman P. Predictors of treatment failure for ec- topic pregnancy

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Ectopic pregnancy (EP) accounts for approximately 75% of deaths in the first trimester, and 9% of all pregnancy-related deaths are the result of EP.

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 were less than 5,000 IU/ml.


Table 1. Relative contraindication to MTX

 \*Sousuke Katoh, Yoko Yoshida, Satoe Fujiwara, Sachiko Kawabe, Mika Hayashi, Atsushi Hayashi, Yoshito Terai and Masahide Ohmichi

MTX Could Be First-Line Therapy Even in Cases Where hCG Level is Greater than 5,000 IU/ml 211

(mIU/ml) Ampurally Interstitial Cervical

<1000 12 - -

1000-1999 7 - -

2000-4999 11 - -

5000-9999 6 2 -

10000-14999 - - 1

>15000 1 4 -

Fourteen cases of ectopic pregnancy, with initial hCG levels >5,000 IU/ml were treated with MTX. Of those 14 cases, 1 had IVF treatment, 1 undertook ovulation induction, and 12 were spontaneous pregnancies. It took 3.85 days from the initial visit to confirm the diagnosis of EP, and the average gestational week was 7.31 weeks. Hospitalization days were 13.57 days,

Fig. 1.

Serum hCG

**3. Results** 

Table 4. Initial serum hCG and pregnancy site


Table 2. Absolute contraindication to MTX


Table 3. Initial hCG level and success rate

#### **2. Materials and method**

We performed MTX treatment in 44 cases, 14 of which were high-hCG EP cases with initial serum hCG levels greater than 5,000 IU/ml. In our department, diagnosis of EP was confirmed, as shown in Figure 1. After getting informed consent for the possibility of additional surgical intervention, we administered MTX IM at a dosage of 50 mg/m2. If a decline of more than 15% was not identified between days 4 and 7, an additional 50 mg/m2 of MTX was administered. Weekly MTX treatment was stopped when hCG levels declined to less than 25 IU/ml (Table 4). Alteration to surgical intervention was adopted according to the patients' requirements.

Fig. 1.

3. Moderate to severe anemia, leukopenia or thrombocytopenia

1. Intrauterine pregnancy

4. Sensitivity to MTX

9. Breast feeding

Table 2. Absolute contraindication to MTX

Table 3. Initial hCG level and success rate

**2. Materials and method** 

the patients' requirements.

Initial serum hCG level(mIU/ml)

5. Active pulmonary disease 6. Active peptic ulcer disease

7. Clinically important hepatic dysfunction 8. Clinically important renal dysfunction

> Success (n=30)

<1000 118 2 98 1000-1999 40 3 93 2000-4999 90 8 92 5000-9999 39 6 87 10,000-14,999 18 4 82

≧15,000 15 7 68

We performed MTX treatment in 44 cases, 14 of which were high-hCG EP cases with initial serum hCG levels greater than 5,000 IU/ml. In our department, diagnosis of EP was confirmed, as shown in Figure 1. After getting informed consent for the possibility of additional surgical intervention, we administered MTX IM at a dosage of 50 mg/m2. If a decline of more than 15% was not identified between days 4 and 7, an additional 50 mg/m2 of MTX was administered. Weekly MTX treatment was stopped when hCG levels declined to less than 25 IU/ml (Table 4). Alteration to surgical intervention was adopted according to

Failure (n=14)

Success rate %

2. Evidence of immunodeficiency


Table 4. Initial serum hCG and pregnancy site

### **3. Results**

Fourteen cases of ectopic pregnancy, with initial hCG levels >5,000 IU/ml were treated with MTX. Of those 14 cases, 1 had IVF treatment, 1 undertook ovulation induction, and 12 were spontaneous pregnancies. It took 3.85 days from the initial visit to confirm the diagnosis of EP, and the average gestational week was 7.31 weeks. Hospitalization days were 13.57 days,

MTX Could Be First-Line Therapy Even in Cases Where hCG Level is Greater than 5,000 IU/ml 213

Therefore, a single dose of MTX was administered. Serum hCG was followed up according to routine, and hCG declined within the normal range after a triple administration (Figure 2).

In the second case, the diagnosis of a right interstitial pregnancy was confirmed by MRI and a and high serum hCG level of 26128 IU/ml. Twice before, the patient experienced ectopic pregnancy followed by surgical intervention so, therefore, therefore MTX treatment was started. However, her serum hCG level elevated to 172 IU/ml following three administrations of MTX following the usual single-dose regiment. Therefore, Actinomycin D at a dosage of 12 μg/kg was administered, and an MTX-resistant ectopic pregnancy was suspected (Figure 3). Post-treatment was uneventful, and the side effect of Actinomycin D

Fig. 2. Time-course of serum hCG level in Case I

and MTX was slight nausea alone.

**Case II** 

and MTX was administered 1.35 times. Implantation sites were 7 ampullary, 6 interstitial, and 1 cervical (Table 5). The range of initial hCG was from 5,713 to 92,670 IU/ml, and the average was 19619.7 IU/ml. More than two administrations of MTX were necessary in 2 cases, one of which was a case of persistent EP. In that case, additional dactinomycin was given. Laparoscopic surgery was adopted in one case of ampullary pregnancy, where initial hCG was 8952 IU/ml (Table 6).

In the following, we present one successful case and one difficult case where additional Actynomycin D was necessary.


Table 5. Clinical outcomes


#### Table 6. Regiment of MTX

#### **Case I**

In the first case, a patient was referred to our hospital for a suspected right interstitial pregnancy. Initial serum hCG was 5979 IU/ml and clinical findings were consistent with the criteria for the diagnosis of an interstitial pregnancy. The patient selected MTX treatment because of her past history with a left salpingectomy for a right ampullary pregnancy. Therefore, a single dose of MTX was administered. Serum hCG was followed up according to routine, and hCG declined within the normal range after a triple administration (Figure 2).

Fig. 2. Time-course of serum hCG level in Case I

#### **Case II**

212 Ectopic Pregnancy – Modern Diagnosis and Management

and MTX was administered 1.35 times. Implantation sites were 7 ampullary, 6 interstitial, and 1 cervical (Table 5). The range of initial hCG was from 5,713 to 92,670 IU/ml, and the average was 19619.7 IU/ml. More than two administrations of MTX were necessary in 2 cases, one of which was a case of persistent EP. In that case, additional dactinomycin was given. Laparoscopic surgery was adopted in one case of ampullary pregnancy, where initial

In the following, we present one successful case and one difficult case where additional

<1000 11(91.6) 2 1(8.4)

1000-1999 6(85.7) 0 1(14.3)

2000-4999 7(63.6) 2 4(34.6)

5000-9999 7(87.5) 2 1(12.5)

>15000 5(100) 2 0(0)

10000-14999 1(100) 0 0(0)

Multiple dose Methotrxate 1 mg per kg intramusculrarly, alternate days

Single dose Methotrxate 50 mg per m2 intramusculrarly. If beta-hCG is

In the first case, a patient was referred to our hospital for a suspected right interstitial pregnancy. Initial serum hCG was 5979 IU/ml and clinical findings were consistent with the criteria for the diagnosis of an interstitial pregnancy. The patient selected MTX treatment because of her past history with a left salpingectomy for a right ampullary pregnancy.

(%) Multiple dose Failure

(days 1, 3, 5, 7) +leucovorin 0.1mg per kg intramuscularly, alternate days (days 2, 4, 6, 8). Continue until beta-hCG falls >15% in 48h or four doses methtorexate. If beta-hCG concentration not <40% of initial value on day 14.

not <15% between days 4 and 7, repeat dose. Up to 4 doses can be given if beta-hCG does not decline by 15% every week.

(%)

Success

Regimen

hCG was 8952 IU/ml (Table 6).

Actynomycin D was necessary.

Serum hCG (mIU/ml)

Table 5. Clinical outcomes

Table 6. Regiment of MTX

**Case I** 

In the second case, the diagnosis of a right interstitial pregnancy was confirmed by MRI and a and high serum hCG level of 26128 IU/ml. Twice before, the patient experienced ectopic pregnancy followed by surgical intervention so, therefore, therefore MTX treatment was started. However, her serum hCG level elevated to 172 IU/ml following three administrations of MTX following the usual single-dose regiment. Therefore, Actinomycin D at a dosage of 12 μg/kg was administered, and an MTX-resistant ectopic pregnancy was suspected (Figure 3). Post-treatment was uneventful, and the side effect of Actinomycin D and MTX was slight nausea alone.

MTX Could Be First-Line Therapy Even in Cases Where hCG Level is Greater than 5,000 IU/ml 215

women who need a second administration avoid surgical intervention (12). The initial level of hCG is the best prognostic indicator of the need for MTX; however, it is still controversial as to what IU should be the cut-point in deciding whether the administration of MTX is necessary. Lipscomb et al. reported that 94% of 350 women whose initial hCG was less than 10,000 IU/ml had success with MTX treatment, therefore suggesting that an initial hCG level greater than 10,000 IU/ml was a factor in the failure of the treatment (12). On the other hand, Gamzu et al. stated that the cut-point to determine the effectiveness of MTX should be lowered to between 2000 mIU/ml and 3000 mIU/ml (16). The hCG incremental rate both before and after MTX represents an independent risk factor for subsequent tubal rupture. Pre-diagnosis concentrations of hCG which increase at least 66% over 48 hours, followed by persistently rising hCG concentrations after treatment with MTX, may lower the threshold

It is widely accepted that above the discriminatory zone of 1,500 IU/l-2500 IU/l, a normal intrauterine pregnancy (IUP) should be visible via TVU. At our clinic, we consider an initial hCG greater than 1500 IU/ml and an invisible GS clear indicators of a possible ectopic pregnancy, and an elevation of hCG greater than 1.5 times in 48 hours without GS confirms the diagnosis. Orivieto et al. reported that single-dose MTX treatment for EP does not have a negative effect on ovarian function nor on the outcome of following IVF-ICSI (18). Paul et al. reported that when hCG is >4000 IU/ml, the failure rate of MTX treatment is 65% (17). In this study, the MTX-failure rate of 14 cases where initial hCG was >5000 IU/ml was 7.1% (1/14); however, the failure rate of low hCG cases <5000 IU/ml was 16.6%. In tubal pregnancy, EP become less vascularized as it invades the tubal serosa, and tubal rupture is likely to occur, compared with that in interstitial pregnancy, before MTX treatment can solve the EP. Compared with cases of tubal pregnancy, the difficulty in diagnosing interstitial pregnancy is thought to be the reason why hCG levels are higher at the time of confirming the diagnosis. However, in our study, 14 cases consisted of 7 ampullary, 6 interstitial and one cervical pregnancy, indicating that tubal pregnancy does not always rupture in high-hCG cases. Therefore, more study is necessary to determine the cut-off for

Recently the cost-effectiveness of treatment has been considered in attempts to save on health insurance costs. Seror reported that, although frequent diagnostic ultrasound is necessary, MTX is cost-effective compared with surgical intervention (10). However, subsequent pregnancies should be followed with extreme caution, and elective cesarean

In conclusion, a serum hCG level greater than 5,000 IU/ml is not necessarily resistant to MTX treatment, and interstitial pregnancy is a particularly good candidate for conservative treatment, even if initial hCG is higher than 5,000 IU/ml. However, MTX failure and tubal rupture was identified irrespective of an initial hCG level of 800 IU/ml in tubal pregnancy. Emergent access to surgical intervention must be made available. As well, the patient's awareness of risk and her availability for admission and surgery are equally important. Therefore, preparation for surgical intervention for emergent situations, even after

[1] Satoe Fujiwara, Yoshiki Yamashita, Sachiko Kawabe, Hideki Kamegai, Yoshito Terai,

Masahide Ohmichi. A case of a methotrexate-resistant ectopic pregnancy in which

for surgical intervention (17).

MTX treatment.

**5. References** 

section should be considered as an alternative.

conservative treatment is determined, is essential.

Fig. 3. Time-course of serum hCG level in Case II
