This document discusses the medical management of ectopic pregnancies. It outlines predictors of success with methotrexate treatment, including initial beta-hCG levels and ectopic mass size. The available options for medical management - single dose methotrexate, multi-dose methotrexate, methotrexate with mifepristone, and hyperosmolar glucose injection - are described and compared. Expectant management is an option for select asymptomatic patients. The document also reviews monitoring, contraindications, complications, costs and challenges to medical management of ectopic pregnancies.

1. ECTOPIC PREGNANCY; MEDICAL
MANAGEMENT
DR. ANTHONY WANJALA
MOI UNIVERSITY SCHOOL OF MEDICINE
ELDORET KENYA
5TH DEC 2012

2. o
o
o
o
What are the predictors of Success?
What are the available options?
Is multi-dose methotrexate superior to single-dose?
Is medical management superior to surgical
management
o Is there room for Expectant management?
o What local challenges do we face?
o What are the financial implications to a patient in
mtrh?

3. Predictors
Initial β hcg
o Pre-treatment value <5,000 IU/L ……success
rates of 92%, >15,000 IU/L …..68% (Lipscomb
et al 1999)
o Pre-treatment β - hCG level >5,000 IU/L were
more likely to require multiple doses of
methotrexate or require surgical intervention.
(Stika and colleagues, 1996)

4. Ectopic pregnancy size
o success rates with single-dose methotrexate
were 93 percent in cases with ectopic masses
<3.5 cm, whereas success rates were between
87 and 90 percent when the mass was >3.5
cm (Lipscomb, 1998)

5. Fetal cardiac activity
o Most studies report increased risk of failure with
cardiac activity.
o Based on limited evidence.
o Success rates of 87 percent have been reported
(Lipscomb, 1998).
o The best candidate for medical therapy is a woman
who is asymptomatic, motivated, and has the
resources to be compliant with treatment surveillance
(Williams Gynecology, 22nd Ed)

6. Contra-Indications
Absolute contraindications for medical therapy as
per the American Society for Reproductive
Medicine, 2006
o Hemodynamic instability
o Inability to remain compliant with post
therapeutic monitoring
o Intrauterine pregnancy
o Breast feeding
o Clinically important hepatic/renal dysfunction.

7. Other Contra-Indications
o
o
o
o
o
Immuno-deficiency
Peptic Ulcer disease
Active Pulmonary disease
Known sensitivity to methotrexate
Alcoholism, Alcoholic liver disease or other chronic
liver disease
o Preexisting blood dyscrasias, such as bone marrow
hypoplasia, leukopenia, thrombocytopenia, or
significant anemia
(ACOG practice bulletin number 94, June 2008)

8. Available options
o Methotrexate
o Methotrexate + Mifepristone
o Hyperosmolar Glucose

9. Methotrexate
o Folic acid antagonist.
o Competitively inhibits the binding of dihydrofolic acid
to dihydrofolate reductase thus ↓ folinic
acid……limited DNA
o Inhibits fast-growing tissue; bone marrow, buccal &
intestinal mucosa, respiratory epithelium, malignant
cells, trophoblastic tissue
o Routes; PO, IV, IM, Local injection
o Side effects: stomatitis, conjunctivitis, and transient
liver dysfunction, myelosuppression, mucositis,
pulmonary damage, and anaphylactoid.

10. Single Dose
Two Dose
Multi-Dose
Dosing
One dose; repeat if necessary
Days 0 and 4
Up to four doses of both drugs
until serum -hCG declines by
15%
Methotrexate
50mg/m2 BSA [day 1]
50 mg/m2 BSA
1 mg/kg, days 1, 3, 5, and 7
Leucovorin
-
-
0.1 mg/kg days 2, 4, 6, and 8
Β hcg
Days 0, 4, 7
Days 0 , 4 and 7. Days 11
and 14 if repeat dose is
given
Days 0 (baseline), 1, 3, 5, and 7
Additional
dose
o If serum -hCG level does
not decline by 15% from
day 4 to day 7
o Less than 15% decline
during weekly surveillance
o If serum -hCG does
not decline by 15%
from day 4 to day 7
o If serum -hCG does
not decline by 15%
from day 7 to day 11
o Maximum of four
doses
If serum -hCG declines <15%,
give additional dose; repeat
serum -hCG in 48 hours and
compare with previous value;
maximum four doses
Surveillance
Weekly until serum -hCG
undetectable
Weekly until serum -hCG
undetectable
Weekly until serum -hCG
undetectable

11. Lipscomb and colleagues (2005) reviewed their
institutional experience with methotrexate
therapy in 643 consecutively treated patients.
They found no differences in
o Treatment duration
o Serum -hCG levels
o Success rates between the multidose and
single-dose protocols, 95 and 90 percent,
respectively.

12. o In the only randomized clinical trial comparing
single and multidose therapy, success rates
between both treatment groups were similar
(89 and 93 percent respectively) (Alleyassin,
2006).

13. Oral Methotrexate
o Bioavailability of oral and parenteral methotrexate is
similar (Jundt, 1993)..
o Korhonen and colleagues (1996) randomly assigned
women with tubal pregnancies without cardiac activity
and serum -hCG levels <5,000 IU/L to receive low-dose
oral methotrexate, 2.5 mg daily for 5 days, or to be
managed expectantly and found no differences in
primary treatment success.
o Bengtsson and associates (1992) gave 15 mg of
methotrexate orally on days 1, 3, and 5 with folinic acid
on days 2, 4, and 6. This was successful in 14 of 15
women with a mean resolution time of 24 days

14. o Following methotrexate administration, up to half of
women experience a short duration of abdominal pain
that can be controlled with nonsteroidal antiinflammatory drugs. This separation pain presumably
results from tubal distention caused by tubal abortion
or hematoma formation or both (Stovall, 1993).
o Sonographic monitoring of ectopic mass dimensions
can be misleading after serum -hCG levels have
declined to <15 IU/L. Brown and colleagues (1991)
have described persistent masses to be resolving
hematomas rather than persistent trophoblastic tissue.

15. Mifepristone Plus Methotrexate
o In a randomized trial of 212 cases, Rozenberg
and co-workers (2003) documented no
differences in success rates.

16. Direct Injection into Ectopic Pregnancy
o In efforts to minimize systemic side effects of
methotrexate, local injection into the
gestational sac under sonographic or
laparoscopic guidance has been evaluated.
o Pharmacokinetic studies with 1 mg/kg of
methotrexate injected either into the sac or
intramuscularly showed similar success rates
but fewer side effects with intragestational
injection (Fernandez, 1994).

17. Hyperosmolar Glucose
o In a small prospective trial, Yeko and colleagues
(1995) reported that direct injection of 50percent glucose into the ectopic mass using
laparoscopic guidance was 94 percent successful
in women with an unruptured ectopic whose
serum -hCG level was <2,500 IU/L.
o Gjelland and co-workers (1995) reported that
treatment success was significantly better in a
similar population in whom sonographic- rather
than laparoscopic-guided injection was used.

18. Surveillance
o Kirk and colleagues (2007) prospectively tested the "day four to
seven" rule in an attempt to predict success at an earlier stage and
ultimately found it superior to all other combinations.
o Bimanual examinations are limited to avoid theoretical risk of tubal
rupture.
o Posttherapy sonography is reserved for suspected complications
such as tubal rupture.
o Repeated liver function tests were not useful in the face of normal
pretreatment values because very few clinically relevant
abnormalities are detected (Lecuru, 2000).
o Contraception is recommended for 3 to 6 months post-therapy as
this drug may persist in human tissues for up to 8 months after a
single dose (Warkany, 1978).

19. Medical versus Surgical Therapy
o Hajenius and colleagues compared a multidose
methotrexate protocol with laparoscopic
salpingostomy and found no differences for tubal
preservation and primary treatment success (Hajenius,
1997).
o Health-related quality of life—pain, posttherapy
depression, and decreased perception of health—was
significantly impaired after systemic methotrexate
compared with laparoscopic salpingostomy
(Nieuwkerk, 1998).
o 61 percent of women undergoing medical therapy
experienced methotrexate complications

20. • Future reproductive potential, as defined by
contralateral fallopian tube patency and
subsequent intrauterine pregnancies, are
similar after medical and surgical therapy
(Buster and Krotz, 2007; Elito, 2006).
• Recurrent ectopic pregnancy rates are
comparable (8 percent to 13 percent) after the
currently accepted methods of treatment
(Buster and Krotz, 2007).

21. Expectant Management
o Distinguishing patients who are experiencimg
sponteneous resolution of their ectopic
pregnancies from patients who have proliferating
ectopic pregnancies is difficult.
o Candidates for expectant management must be
willing to accept the potential risks of rupture &
haemorrhage. Should be asymptomatic & have
objective evidence of resolution [decreasing hcg].
o Approx 20 – 30 % of patients present with
decreasing hcg. [Shalev et al, 1995]

22. o If the initial hcg is < 200 mU/mL 88-96% of
patients experience sponteneous resolution
whereas values >2,000 IU/L had success rates of
only 20 to 25 percent (Elson, 2004; Trio, 1995)
o Reasons for abandoning expectant management
include intractable or significantly increased pain,
failure of hcg to decrease and tubal rupture with
haemoperitoneum.

23. Isoimmunization
o If the woman is D-negative and her partner
has a blood group that is either D-positive or
unknown, then 300 g anti-D immune globulin
should be given intramuscularly to prevent
anti-D isoimmunization

24. Gross financial estimates
MEDICAL MX [KES]
SURGICAL MX [KES]
Admission
200
200
Basic Investigations
X + 1700
X
β hcg
*4 = 9200
-
Methotrexate
Single dose = 550
-
Average Length of stay
2 days = 700
3 days = 1050
Theatre fee
-
7500
Post-op Meds
-
1500
Out-patient follow-up
*3 = 600
*1 = 200
Total
X + 12950
10450
Difference
- 2500
+ 2500

25. Local challenges
o Majority of patients present with ruptured
ectopic.
o Un-reliable labs values.
o Beta hcg only done on Fridays.
o Poor follow up structures.