This study compared the efficacy of double-dose and single-dose methotrexate protocols for treating ectopic pregnancies. It found: 1. The overall success rate was higher but not significantly different for the double-dose protocol (88%) compared to the single-dose protocol (82%). 2. The double-dose protocol had significantly higher success rates than the single-dose protocol for patients with initial β-hCG levels between 3600-5500 mIU/ml and ectopic mass diameters between 2.7-3.5 cm. 3. The double-dose protocol may be more effective for patients with higher β-hCG levels and larger ectopic mass sizes because the closer proximity

1. Comparison Of Double & Single-
dose Methotrexate Protocols For
Treatment Of Ectopic Pregnancy
Salah Roshdy Ahmed a, MD; Hossam O
a b
Hamed , MD; Abullah A Alghasham, MD
Departments of Obstetrics and Gynecology a and
b
Pharmacology
College of Medicine, Qassim University
2012/2013

2. INTRODUCTION

3. 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.

4. 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.

5. 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?

6. 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)

7. 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.

8. 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.

9. 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.

10. Aim of the study

11. 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.

12. Patients and Methods

13. 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.

14. 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.

15. 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.

16. 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.

17. Patients assessed for
Participants eligibility (n = 189)
flow chart Total excluded patients due to
Enrollment presence of exclusion criteria
or refusal to take
methotrexate: n=32
Randomization
(n= 157)
Group (1) (n= 79) Group (2) (n= 78)
Received double-dose Received single-dose
regimen (50 mg/m2 IM regimen (50 mg/m2 IM on
on day 0 and 4) day 0)
Follow up for negative
β-hCG or 6 weeks,
which comes first
-Patients had persistence or< 15 %
drop of β-hCG between day 4 and day
Patients had > 15 % drop of β-
7. or
hCG between day 4 and day 7
-Persistent serum pregnancy test
and negative serum pregnancy
positive beyond 6 weeks. or
test within 6 weeks.
-Surgical intervention due to
suspected tubal rupture
Successful Failed
Treatment Treatment

18. 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.

19. 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.

20. RESULTS

21. Demographic and baseline criteria in both
groups.
Baseline criteria Group 1 Group 2 Pa
(n =79) (n =78) value
Patient age (years) mean ± SD (range) 23.1 ± 6.5 (19-35) 25.4 ± 4.7 (18-36) .3
BMI mean ± SD (range) 25.6 ± 8.4 ( 20-39) 26.21 ± 7.7 (22-38) .6
Parity : 29 (36.7) 25 (32.1) .6
1 (%) 31 (39.2) 36 (46.1)
2 (%) 19 (24.0) 17 (21.8)
>2 (%)
History of spontaneous abortion (%) 21 (26.5) 24 (30.7) .8
History of previous ectopic pregnancy (%) 7 (8.8) 6 (7.6) .2
History of ovulation induction (%) 12 (15.0) 10 (12.8) .1
History of IVF (%) 4 (5.0) 6 (7.6) .2
Gestational age (days) mean ± SD (range) 43.4 ± 17.1( 35-58) 45.1 ± 14.9 (37-62) .4
hCG (mIU/ml) mean ± SD 3565.8 ± 1977.6 3158.4 ± 1462.4 .1
(range) (550 – 9200) (450 – 8800)
Longest ectopic mass diameter (cm) 2.7 ± 0.9 (0.5 – 4.0) 2.6 ± 0.8 (0.8 –4.0) .6
mean ± SD (range)
Patients presented by pelvic pain (%) 16 (20.2) 17 (21.7) .7
Patients presented by vaginal bleeding (%) 14 (17.7) 13 (16.6) .9

22. Study outcomes in both groups
Outcome Group 1 Group 2 Relative risk P
(n =79) (n = 78) OR (95% CI) Value
Overall success rate (%) 70/79 (88.6) 64/78 (82.1) 1.70 (0.68-4.2) .1
Follow up duration (days) in
successfully-treated patients
Mean ± SD (range) 20.3±4.8 (15-32) 31.0±6.7 (21-42) - .001
Methotrexate adverse
effects:
Overall complication rate 24/79 (30.4) 20/78 (25.6) 0.79 (0.39–1.58) .5
-New-onset abdominal pain 7 (8.8) 6 (7.7) - -
-Gastrointestinal symptoms 6 (7.5) 4 (5.1) - -
-Mucositis 4 (5.0) 3 (3.8) - -
-loss of hair 1 (1.3) 2 (2.6) - -
-Elevated liver enzymes e 4 (5.0) 3 (3.8) - -
-Thrombocytopenia/ 2 (2.5) 2 (2.6) - -
Leucopenia

23. ROC curve for serum β-hCG and longest gestational
mass length in relation to successful outcome in
group (1).
ROC curve analysis shows: Figure 2-A: ROC Curve in group 1
1.00
• at β-hCG cut-off level ≤
5500 mIU/ML, the sensitivity .75
and specificity for success
were 81% and 89% (area
.50
under curve is 0.822), also
• at mass diameter cut-off ≤ Reference Line
Sensitivity
.25
3.5 cm the sensitivity and
Mass length
specificity for success were
0.00 B-hCG
73% and 78%, (area under 0.00 .25 .50 .75 1.00
curve is 0.813)
1 - Specificity
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

24. ROC curve for serum β-hCG and longest gestational
mass length in successful outcome in group (2).
ROC curve analysis shows:
Figure 2-B: ROC Curve in group 2
• at β-hCG cut-off level ≤ 1.00
3600 mIU/ML, the sensitivity
and specificity for success .75
outcome were 75% and
86% (area under curve is
.50
0.768).
• at mass diameter cut-off ≤ Reference Line
Sensitivity
.25
2.7 cm the sensitivity and
Mass length
specificity for success were
0.00 B-hCG
72% and 71% (area under 0.00 .25 .50 .75 1.00
curve is 0.79).
1 - Specificity
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

25. Success rate in relation to baseline β-hCG
ectopic mass diameter in both groups
Outcome Group 1 Group 2 Relative risk P
(n =79) (n = 78) OR (95% CI) Value
Success rate in relation to:
Baseline β-hCG (mIU/ml):
- < 3600 33/35 (94.3) 48/50 (96.0) 0.68 (0.09-5.1) 1.0
- 3600- 5500 24/27 (88.9) 11/19 (57.9) 5.80 (1.29-26.2) .03
> 5500 13/17 (77.5) 5/9 (55.6) 2.60 (0.46-14.6) .3
Ectopic mass diameter (cm):
- < 2.7 37/40 (92.5) 45/46 (95.7) 0.56 (0.08-3.5) .6
- 2.7-3.5 21/23 (91.3) 12/19 (63.2) 6.12 (1.09-34.3) .05
- > 3.5 12/16 (75.0) 8/13 (61.5) 1.87 (0.38–9.1) .6

26. 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.

27. Summary

28. 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.

29. 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

30. 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

31. 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.

32. 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.

34. Any Question ?