Comparison Of Double & Single-

dose Methotrexate Protocols For

Treatment Of Ectopic Pregnancy

Salah Roshdy Ahmed a, MD; Hossam O

Hamed a, MD; Abullah A Alghasham, b MD

Departments of Obstetrics and Gynecology a

and

Pharmacology b

College of Medicine, Qassim University 2012/2013

INTRODUCTION

Introduction

• Ectopic pregnancy complicates 2-5% of all

pregnancies and carries significant risks for

maternal health.

• More than 90% of cases are sited in the Fallopian

tube resulting in tubal rupture with development of

hemoperitoneum after few days or weeks from

missed menstrual period.

• In early-diagnosed cases and before tubal

rupture, we have the opportunity to manage the

patient medically by methotrexate instead of

surgical intervention.

Introduction

• The medical treatment by methotrexate has been

developed in the last decade and accepted as

first-line treatment or a cost-effective alternative to

laparoscopy in well-selected patients .

• Among multiple methotrexate protocols, multi-

dose regimen includes IM administration of 4

methotrexate doses alternating with folinic acid in

a course that extends for 8 days. While single-

dose protocol comprises single dose

administration which could be repeated weekly up

to 4 weeks in poor-responders.

Introduction

• The potential advantages of single protocol over

multi-dose one are elimination of folinic acid use,

lower incidence of side effects, and better

compliance and convenience.

• Although the efficacy of both methotrexate

regimens had been studied extensively, there is

no consensus for optimum Protocol.

Why?

Introduction

• The single-dose protocol in a large meta-analysis

conducted by Barnhart et al in 2003 was

associated with significantly lower success rate

compared with multi-dose regimen (88% vs. 93%).

But, these data were not proved in multiple

subsequent studies which showed comparable

success rates in both regimens. (Lipscomb et al 2005

and Alleyassin et al 2006)

Introduction

• On the other hand, the outcome of single-dose

regimen is inconsistent in multiple studies

depending on initial β-hCG level, gestational

mass size, and the number of repeated

dosages.

• A success rate as low as 35% with β-hCG >

4000 IU/L and as high as 98% with levels <

1000 IU/L was previously reported.

Introduction

• The challenge to develop an optimum regimen

that balance between efficacy and safety in one

side and convenience in other side was

attempted by Barnhart et al (2007)who first

described what is called double-dose protocol.

• In his study that included 101 patients, 2 doses

of methotrexate were administered at day 0 and

4 without measuring β-hCG between doses and

reported 76% success rate.

Introduction

• Although their reported rate is comparable

to that of single-dose regimen, there are no

clinical trials in literature have compared

both regimens.

• We hypothesize that efficacy of double-dose

protocol could be more effective than non-

repeated single-dose regimen especially in

patients with high baseline β-hCG and large

gestational mass.

Aim of the study

Aim of the work

• The aim of this study was to assess the efficacy

and safety of double-dose regimen in which

methotrexate is given alone and only at day 0

and 4 to non-repeated single dosage at day 0 in

patients with tubal EP.

• The end-points for comparison are:

1. Success rate,

2. Duration of follow up until complete resolution,

and

3. Methotrexate adverse effects.

Patients and Methods

Inclusion criteria

Diagnosis of EP was diagnosed with non-laparoscopic

algorithm

(Stovall et al 1990).

The inclusion criteria were:

1) Gestational mass in adnexa with maximum diameter ≤ 4

cm;

2) Baseline β-hCG <15000 mIU/ml;

3) Hemodynamically stable patients;

4) Absence of gestational cardiac activity

5) Patients agreed to methotrexate therapy and follow-up.

Exclusion criteria

We excluded patients with:

1) Non-tubal EP

2) Clinically suspected tubal rupture;

3) Free fluid at TVS extending beyond Douglas pouch;

4) Low platelet count or abnormal liver or kidney functions.

Sample size

• Sample size calculation was based on the biggest

difference reported between success rates of non-

repeated double and single-dose protocols. The lowest

success rate of one-dose regimen and the highest

success rate of double-dose protocol in unselected

population with adnexal EP were 65% and 76%,

respectively (Barnhart et al 2007).

• A total of 152 patients were required to find this 11%

difference with statistical significance setting α at 0.05

and β at 0.2.

Randomization

• Enrolled patients were randomized to either

– group (1) which received non-repeated double-

dose methotrexate regimen in a dose of 50

mg/m2 IM on day 0 and day 4] (Barnhart et al

2007) or

– group (2) whose patients had the same dosage

once on day 0 (Stovall and Ling 2003).

• Randomization was performed using a computer-

generated random numbers table.

Group (1) (n= 79)

Received double-dose

regimen (50 mg/m2 IM

on day 0 and 4)

-Patients had persistence or< 15 %

drop of β-hCG between day 4 and day

7. or

-Persistent serum pregnancy test

positive beyond 6 weeks. or

-Surgical intervention due to

suspected tubal rupture

Group (2) (n= 78)

Received single-dose

regimen (50 mg/m2 IM on

day 0)

Patients assessed for

eligibility (n = 189)

Total excluded patients due to

presence of exclusion criteria

or refusal to take

methotrexate: n=32

Enrollment

Randomization

(n= 157)

Follow up for negative

β-hCG or 6 weeks,

which comes first

Successful

Treatment

Failed

Treatment

Patients had > 15 % drop of β-

hCG between day 4 and day 7

and negative serum pregnancy

test within 6 weeks.

Participants

flow chart

Management of failures

• Further management of patients with treatment

failure was arranged but not counted in current

results. Failures of group (1) was managed by

elective surgical intervention while in group (2)

the choice of repeating methotrexate dosage or

surgical intervention was based on discretion of

the physician and patient wishes.

Statistical analysis plain – Student-t- test was used to compare means

while the 2 or Fisher exact tests were used

when appropriate to compare the dichotomous

variables.

– Receiver operator characteristics (ROC) curves

for initial β-hCG concentration and longest

ectopic mass diameter was created to establish

cut-off points that associated with success in

both groups.

– P value <0.05 was considered statistically

significant.

RESULTS

Demographic and baseline criteria in both

groups. P a

value

Group 2

(n =78)

Group 1

(n =79)

Baseline criteria

.3 25.4 ± 4.7 (18-36) 23.1 ± 6.5 (19-35) Patient age (years) mean ± SD (range)

.6 26.21 ± 7.7 (22-38) 25.6 ± 8.4 ( 20-39) BMI mean ± SD (range)

.6 25 (32.1)

36 (46.1)

17 (21.8)

29 (36.7)

31 (39.2)

19 (24.0)

Parity :

1 (%)

2 (%)

>2 (%)

.8 24 (30.7) 21 (26.5) History of spontaneous abortion (%)

.2 6 (7.6) 7 (8.8) History of previous ectopic pregnancy (%)

.1 10 (12.8) 12 (15.0) History of ovulation induction (%)

.2 6 (7.6) 4 (5.0) History of IVF (%)

.4 45.1 ± 14.9 (37-62) 43.4 ± 17.1( 35-58) Gestational age (days) mean ± SD (range)

.1 3158.4 ± 1462.4

(450 – 8800)

3565.8 ± 1977.6

(550 – 9200)

hCG (mIU/ml) mean ± SD

(range)

.6 2.6 ± 0.8 (0.8 –4.0) 2.7 ± 0.9 (0.5 – 4.0) Longest ectopic mass diameter (cm)

mean ± SD (range)

.7 17 (21.7) 16 (20.2) Patients presented by pelvic pain (%)

.9 13 (16.6) 14 (17.7) Patients presented by vaginal bleeding (%)

Study outcomes in both groups

P

Value

Relative risk

OR (95% CI)

Group 2

(n = 78)

Group 1

(n =79)

Outcome

.1 1.70 (0.68-4.2) 64/78 (82.1) 70/79 (88.6) Overall success rate (%)

.001

-

31.0±6.7 (21-42)

20.3±4.8 (15-32)

Follow up duration (days) in

successfully-treated patients

Mean ± SD (range)

.5

-

-

-

-

-

-

0.79 (0.39–1.58)

-

-

-

-

-

-

20/78 (25.6)

6 (7.7)

4 (5.1)

3 (3.8)

2 (2.6)

3 (3.8)

2 (2.6)

24/79 (30.4)

7 (8.8)

6 (7.5)

4 (5.0)

1 (1.3)

4 (5.0)

2 (2.5)

Methotrexate adverse

effects:

Overall complication rate

-New-onset abdominal pain

-Gastrointestinal symptoms

-Mucositis

-loss of hair

-Elevated liver enzymes e

-Thrombocytopenia/

Leucopenia

ROC curve for serum β-hCG and longest gestational

mass length in relation to successful outcome in

group (1).

Figure 2-A: ROC Curve in group 1

B-hCG: area under curve = 0.822. SE = 0.06. P = 0.002

Mass length: area under curve = 0.813. SE = 0.07. P = 0.002

1 - Specificity

1.00.75.50.250.00

Sensitiv

ity

1.00

.75

.50

.25

0.00

Reference Line

Mass length

B-hCG

ROC curve analysis shows:

• at β-hCG cut-off level ≤

5500 mIU/ML, the sensitivity

and specificity for success

were 81% and 89% (area

under curve is 0.822), also

• at mass diameter cut-off ≤

3.5 cm the sensitivity and

specificity for success were

73% and 78%, (area under

curve is 0.813)

ROC curve for serum β-hCG and longest gestational

mass length in successful outcome in group (2).

Figure 2-B: ROC Curve in group 2

B-hCG: area under curve = 0.768. SE = 0.06. P = 0.002

Mass length: area under curve = 0.790. SE = 0.06. P = 0.001

1 - Specificity

1.00.75.50.250.00

Sensitiv

ity

1.00

.75

.50

.25

0.00

Reference Line

Mass length

B-hCG

ROC curve analysis shows:

• at β-hCG cut-off level ≤

3600 mIU/ML, the sensitivity

and specificity for success

outcome were 75% and

86% (area under curve is

0.768).

• at mass diameter cut-off ≤

2.7 cm the sensitivity and

specificity for success were

72% and 71% (area under

curve is 0.79).

Success rate in relation to baseline β-hCG

ectopic mass diameter in both groups

P

Value

Relative risk

OR (95% CI)

Group 2

(n = 78)

Group 1

(n =79)

Outcome

1.0

.03

.3

.6

.05

.6

0.68 (0.09-5.1)

5.80 (1.29-26.2)

2.60 (0.46-14.6)

0.56 (0.08-3.5)

6.12 (1.09-34.3)

1.87 (0.38–9.1)

48/50 (96.0)

11/19 (57.9)

5/9 (55.6)

45/46 (95.7)

12/19 (63.2)

8/13 (61.5)

33/35 (94.3)

24/27 (88.9)

13/17 (77.5)

37/40 (92.5)

21/23 (91.3)

12/16 (75.0)

Success rate in relation to:

Baseline β-hCG (mIU/ml):

- < 3600

- 3600- 5500

> 5500

Ectopic mass diameter (cm):

- < 2.7

- 2.7-3.5

- > 3.5

Tubal rupture rate

On failure side, we had 2 patients (2.5%) out of 9

counted as failures in double-dose developed

tubal rupture during first week of starting

methotrexate. This is compared to 3 patients

(3.8%) out of 14 failures in one-dose regimen.

Summary

Overall success rates

• This trial demonstrated higher but insignificant

overall success rate with double-dose regimen

(88% vs. 82%). This rate is higher than Barnhart et

al who first described double-dose protocol and

reported 76% in his study that included 101

patients.

• The overall success rate of current one-dose

treatment is comparable to others reported 65-96%

depending on number of repeated doses and initial

β-hCG concentration.

Success rates in subgroups

Why double-dose regimen is more effective in the subgroups with

high β-hCG and large ectopic mass?

• The larger the size of ectopic mass the higher possibility of

β-hCG production and the higher methotrexate dose

required to control active trophoblastic cells.

• The double-dose protocol has the potential advantage of

close proximity of second to first dose; a factor that highly

suggested to enhance its effect on patients with high

trophoblastic-cell load

Success rates in subgroups

• This could explain the reported higher cut-off points of β-hCG and ectopic mass diameter that associated with success in double-dose regimen compared to single-dose.

• The significant difference in success rates between groups was lost when β-hCG exceeded 5500 mIU/Ml and the mass diameter exceeded 3.5 cm which suggests the possibility of an upper limit of trophoblastic mass that is sensitive to methotrexate treatment

Adverse effects of Methotrexate

• The types and frequency of methotrexate adverse effects in current study are comparable in both groups (30% vs. 26%) and similar to others reported 25-32%.

• The most frequent adverse effect was pelvic pain (8.8% vs. 7.7%) which is mostly caused by resolving EP rather than methotrexate itself.

• The low rate of adverse effects with current double-dose regimen should be taken carefully as an indicator for safety of using 2 methotrexate doses, 4 days apart, without folinic acid rescue.

Conclusion and recommendation

• In conclusion, double-dose protocol is an efficient

and safe alternative for one-dose regimen. It is more

effective, within limits, in patients with high initial β-

hCG and large ectopic mass.

• We recommend conducting randomized trials with

adequate power to compare both regimens on

selected population with potential risks for

methotrexate failure to establish an effective

management protocol in those patients.

Any Question ?