Transcript MtX versus Prostaglandins both transvaginally under U/S guidance

JOURNAL CLUB:
REVIEW OF EVIDENCE ON
INTERVENTIONS FOR TUBAL ECTOPIC
PREGNANCY—METANALYSIS RESULTS
Heena Mehra
Caroline Fox
ECTOPIC PREGNANCY
Approx 1 %of fertilized eggs—extrauterine pregnancies
 Occurs anywhere along the reproductive tract
 Commonest site Fallopian tube
 Tubal ectopics, if not treated, causes rupture/bleeding
and can be fatal.
 Treatment options:

Surgery
 Medical Treatement
 Expectant Management

BACKGROUND : MANAGEMENT STRATEGIES


Much advancement in early diagnosis of ectopic
pregnancies non invasively (physical /ultrasound /
laboratory findings) & successful therapeutic
interventions.
Ankum 1995; Condus 2004; Condous 2005
Surgical Strategies:

Salpingostomy vs salpingectomy
Tubal integrity preserved for future fertility in salpingostomy
 But hazard of incomplete removal of trophoblastic tissue Siefer 1990
 Serum hCG monitoring thus strongly recommended to detect
persistent trophoblast
Hajenius 1995; Spandorfer 1997

Laproscopic Salpingostomy
 Open Salpingostomy

BACKGROUND : MANAGEMENT STRATEGIES

Medical Strategies:

Focus of research (as Diagnostic Lap obsolete) on selecting subest
of tubal ectopic pregnancies for non-surgical option and avoid
risk to patients.
Tulandi 1991b; Hochner 1992; Maymon 1996

Systemic & local Administration of drugs

Most common drug used—Methotrexate




Folic acid antagonist
Strong dose related secondary cytotoxicity
Usually given in Fixed multiple dose (Bagshawe 1989; Goldstein 1976) or variable
dose / single dose intramuscular regimen. (Stovall 1991; Stovall 1993).
Local medical treatment strategies developed to minimise
adverse effects and attain maximal efficacy



Transvaginally under U/S guidance
Laproscopic guidance
Drugs used Methotrexate (Pansky 1989; Fernandez 1993) , prostaglandins
(Lindblom 1987; Egarter1988) and hyperosmolar glucose (Lang 1989)
BACKGROUND:MANAGEMENT STRATEGIES
Expectant Mx First reported & practiced by Lund
in 1955
 Advocated on knowledge that
many ectopic
pregnancies undergo a natural course with self
limiting process –tubal abortion or reabsorption

Mashiach 1982

Only few studies published describing expectant
management in selected patients:
Small ectopic pregnancies without fetal cardiac activity
 Upper limit for serum hCG levels that continue to decline
 Low serum progesterone levels

Korhonen 1994; Hajenius1995b; Elson 2004
QUESTIONS

Which treatment option most effective & safe?

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
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
Laproscopic Salpingostomy vs Open Surgery
Surgery vs medical management
Systemic Medical treatment vs Local
Combination approach vs Medical only
Role of expectant management.
How important are secondary outcomes with
patient’s QoL, Financial costs, tubal preservation
and future fertility with these treatments.
REVIEW OF EVIDENCE-A METANALYSIS
REPORT
Interventions for tubal ectopic pregnancy
Petra J Hajenius, Femke Mol, BenWillem J Mol,
Patrick MM Bossuyt, Willem M Ankum, Fulco
Van der Veen
Academic Medical Centre, O&G, University of Amsterdam
Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000324.
DOI: 10.1002/14651858.CD000324.pub2.
STUDY REVIEW CHARACTERISTICS

Type of studies evaluated—
Only RCTs
one treatment with
other in m/m of ectopic
pregnancies.
 Only where allocation was
randomised.
 Non-randomised controlled trials
were excluded.

Primary Outcome:

 comparing
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Secondary outcomes:




Types of interventions:
 Type
of Surgery
 Drugs used for medical
treatment
 Dosage & route of
administrations of medical
treatment.
 Expectant management.
Treatment success by initial
treatment



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Persistent trophoblast
Tubal preservation
Complication/side effects
Costs
Tubal patency
Patients’ health related
quality of life
Future fertility
35 RCTs evaluated describing 25 different comparisons:
Analysed studies published upto 2006
 Surgery:
Laparoscopic salpingostomy versus salpingostomy by open
surgery (Vermesh 1989; Lundorff 1991a; Lundorff 1991b; Lundorff 1992; Vermesh 1992; Gray 1995)
 Mini-laparotomy versus laparotomy (Sharma 2003)
 Salpingostomy without tubal suturing versus salpingostomy
with tubal suturing (Tulandi 1991a; Fujishita 2004)
 Salpingostomy alone versus salpingostomy combined with
medical treatment

a. with a single dose intramuscular methotrexate (Graczykowski 1997;
Elmoghazy 2000)
b. with an intramesosalpingeal injection vasopressin (Ugur 1996)
c. with an intra mesosalpingeal injection oxytocin
(Fedele 1998)
MEDICAL TREATMENT:
MTX vs Surgery

Systemic methotrexate versus laparoscopic salpingostomy
a. in a fixed multiple dose intramuscular regimen (Hajenius 1997;Nieuwkerk 1998a;
Dias Pereira 1999; Mol 1999a)
b. in a variable dose intramuscular regimen (Fernandez 1998; Saraj1998; Sowter 2001a;
Sowter 2001b; El-Sherbiny 2003)

Local methotrexate versus laparoscopic salpingostomy
a. Transvaginally under U/S guidance (Fernandez 1995; Fernandez 1998)
b. Under laparoscopic guidance (Mottla 1992; Zilber 1996)
Methotrexate via different administration routes
Transvaginally under U/S guidance versus under
laparoscopic guidance (Tzafettas 1994)
 Transvaginally under U/S guidance versus single dose
intramuscular (Fernandez 1994; Fernandez 1998; Cohen 1996)
 Under laparoscopic guidance versus the same regimen in
combination with systemic intramuscular methotrexate

(Shulman 1992)
Methotrexate different dosage/suspension
Hyperosmolar glucose
 Single dose versus fixed multiple dose
 Hyperosmolar glucose intratubal under
both by intramuscular administration
laparoscopic guidance versus other
(Klauser 2005; Alleyassin 2006)
treatments
a. versus local methotrexate under laparoscopic
 25
mg/m2 methotrexate versus the
guidance
(Sadan 2001)
standard 50 mg/m2 methotrexate both in
b. versus hyperosmolar glucose transvaginally
a single dose intramuscular regimen
under sonographic guidance
(Yalcinkaya 1996; Yalcinkaya 2000)

In lipiodol suspensions versus in saline
both under laparoscopic guidance
(Fujishita 1995b)
(Gjelland 1995; Hordnes 1997)
c. versus local and systemic prostaglandins
(Lang 1990)
d. together with local prostaglandins versus
methotrexate in a oralregimen
(La ndstrom 1998)


Methotrexate versus/or in combination
with other medical treatments
Expectant management
Methotrexate versus prostaglandins both
transvaginally
under
sonographic Expectant management versus medical
guidance combined with the systemic treatment
administration of the drug (Fernandez 1991)
a. versus systemic methotrexate in a low dose
oral regimen
(Korhonen 1996)
Systemic methotrexate in a single dose
b.
versus
local
and
systemic
prostaglandins
intramuscular regimen alone versus in
(Egarter 1991)
combination with oral mifepristone
(Gazvani 1998; Rozenberg 2003)

Systemic methotrexate in a single dose
intramuscular regimen alone versus in
combination with Ectopic Pregnancy 2
(EP2) decoction (Chinese herb) (Wang 1998)
RISK OF BIAS
Overall Methodological risk of bias considered
suboptimal, due to lack of detailed info on
allocation & randomisation in >50% studies.

Method of randomisation


Allocation concealment


11/35 studies described concealed allocation
Blinding


19/35 trials described method of allocation & all 35 stated
occurrence of randomisation
Not applicable in most studies
Sample Size
All studies had small sample sizes. Only 6 studies had >
100 women
 Metanalysis done for 8 comparisons involving 60-265
women.

RESULTS
Laproscopic Salpingostomy versus Open Salpingostomy

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Vermesh 1989; Lundorff 1991a showed Lap Salpingostomy to be
significantly less successful than the open surgical approach
(OR 0.28, 95% CI 0.09 to 0.86) —due to significantly higher
persistent trophoblast rate of laparoscopy surgery (OR 3.5,
95%CI 1.1 to 11).
Laproscopic Sx less costly than open Sx (Gray 1995) —due to
significant shorter operation time, less peri-operative blood
loss, shorter duration of hospital stay (1-2 vs 3-5 days,P<0.01) &
shorter convalescence time (11vs 24 days, p<0.001).
Non significant tendency to a lower tubal patency rate after
laparoscopic surgery (OR 0.58) in 110 women after a follow up of 1 -24
weeks (Vermesh 1989; Lundorff 1991b)
No e/o difference in rates of subsequent intrauterine pregnancies, but
non significant lower rates of repeat ectopics in laproscopic group( OR
0.47)
RESULTS
Minilaprotomy versus laprotomy Salpingostomy
Sharma 2003 showed 100% success rates in all
patients with either approach
 Postoperative complications were significantly less in
minilap group (paralytic ileus 10% vs 27%, P=0.045; wound infection 3%

vs 17%, P=0.045)

Parameters of costs were significantly less in minilap
group (p=0.033) in terms of mean operative time and
hospital stay.
Salpingostomy without tubal suturing vs
Salpingostomy with tubal suturing
 Non significant tendency to a lower treatment success
(OR 0.16) and lower tubal patency rate (OR 0.38) after
salpingostomy without tubal suturing as shown in a
study on 109 women by Tulandi 1991a; Fujishita 2004.

No difference was noted on number of subsequent
intrauterine pregnancies (OR1.1) & number of repeat
ectopic pregnancies (OR 1.2).

Salpingostomy alone vs combined with Medical treatment
With single dose IM Mtx (1mg/kg with 24hrs postoperatively)
Graczykowski 1997; Elmoghazy 2000

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Prophylactic use significantly lowers persistent Trophoblastic rate (OR
0.25)
However NNT is 10 to prevent 1 woman with persistent trophoblast
With Intra mesosalpingeal vasopressin


Non significant tendency of lower treatment success without vasopression,
due to increased open surgery conversion from excessive bleeding. (OR
0.35)
With Intra mesosalpingeal oxytocin



Ugur 1996
Fedele 1998
Small study (multicentre) showed significantly reduced bleeding with an
easier removal of tubal ectopic pregnancy without side effects (p<0.005)
But these results not reflected in primary treatment success (OR 0.15)
RESULTS: MEDICAL TREATMENT
Systemix MtX vs Laproscopic Salpingotomy
1. Fixed Multiple dose I.M.regimen (1mg/kg od D 0,2,4,6 alternated with Folinic
acid 0.1mg/kg P.O. D 1, 3, 5, 7)



Haejenius 1997
Mean hCG levels in MtX arm were 1950IU/l
Non significant tendency to higher treatment success with MtX arm(OR 1.8)
However, 61% of patients receiving Methotrexate experienced
complications/side effects compared to just 12% in salpingostomy group.

Health related QoL significantly impaired after systemic MtX
(P<0.05)
Nieurwark 1998a

Cost wise systemic MtX appears to be more expensive.

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

Mol 1999a
Due to re-intervention with surgical treatment in some women causing
prolonged hospital stay (4.5 vs 2.5 days), loss of productivity.
Re-interventions only required in women with initial Sr. hCG >1500 IU/l .
Costs in MtX group were found to be non significantly lower in women with
hCG <1500 IU/l and equal in women with initial serum hCG levels between
1500-3000 IU/l.
Tubal patency rates, spontaneous intrauterine pregnancies or
repeat ectopic pregnancies rates did not differ.
Dias Pereira 1999
SYSTEMIX MTX VS LAPROSCOPIC SALPINGOTOMY
2. Variable Dose Intramuscular MtX regimen

Single dose MtX (50mg/m2 or 1mg/kg) was used in 4 studies involving
265 women with a small unruptured ectopic pregnancy–
Fernandez 1998; Saraz 1998; Sowter 2001a/b; El-Shirbiny 2003
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Criteria used in studies were:
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Significantly less successful than Lap salpingostomy (OR 0.38)
This was due to inadequately declining serum hCG, for which additional
MtX doses had to be given. (OR 3.3).
With a variable dose MtX regimen—treatment success rates rises, but
shows no difference compared with lap salpingostomy.(OR1.1)
Increased rates of adverse effects seen in MtX arm compared to Lap Sx
group.
Sowter 2001a
Upper limit of serum hCG (<5000IU/l , Sowter 2001a, <10000 IU/l El-Sherbiny 2003)
Absence of positive fetal heartbeat
Small size of tubal ectopic (<3.5cm)
Subgroup analysis shows significant higher costs in women with
initial serum hCG >1500 IU/l.
LOCAL METHOTREXATE VS LAP SALPINGOSTOMY

Transvaginally under U/S guidance (MtX 1mg/kg):


Significantly less successful (OR 0.17) compared to Lap Sx—Due
to higher persistent trophoblast rate (OR 4.9)
Fernandez 1998
Local MtX under laproscopic guidance (Mtx 25mg):
2 studies with total 60 patients
 Non significantly lower success rates seen in MtX arm
 Additional surgical interventions did not affect tubal preservation
rates. (OR 0.16)
 Non significant difference was found for subsequent intrauterine
pregnancies (OR 0.87) with a non significant lower repeat ectopic
pregnancy rates (OR 0.15)
Mottla 1992; Zilber 1996

METHOTREXATE VIA DIFFERENT ADMINISTRATION ROUTES

T/V under U/S guidance vs Laparoscopic guidance:


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36 patients had 100mg MtX
Transvaginal administration under U/S guidance was
significantly better than the ‘blind’ intra tubal injection
under Lap guidance. (OR 5.8)
Tzafettas 1994
T/V under U/S guidance versus intramuscular dose
3 studies with 95 women
 Non significant tendency to a higher treatment success after local
MtX transvaginally. (OR 2.14)
 I.U pregnancy rates and repeat ectopic rates were similar in all
these women.
Fernandez 1994; Cohen 1996; Fernandez 1998

METHOTREXATE DIFFERENT DOSAGE/SUSPENSION
Single dose (50mg/m2) versus fixed multiple dose (1mg/kg) by IM
route
Klauser 2005; Alleyassin 2006
2 studies with 159 women
 No significant difference in primary success rates(OR 0.89)
 Alleyassin 2006 showed 37% rates of side effects in multiple
dose versus 27% in single dose group (P=0.3)
 However, Klauser 2005 contradictorily showed minor s/e of 28%
in single dose group versus 10% in multiple dose group (P=0.2).

25mg/m2 versus standard 50mg/m2 in single dose I.M.
Double blind study with 100 patients
 Non significant lower treatment success in lower dose group
(OR 0.68)
 Side effects did not differ in both groups
 Tubal patency rates and future fertility rates did not differ.

Yalcinkaya 1996; Yalcinkaya 2000
METHOTREXATE VS/OR IN COMBINATION
WITH OTHER MEDICAL TREATMENTS


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MtX versus Prostaglandins both transvaginally under U/S guidance with
systemic administration of the Drug:
 Fernandez 1991 showed no significant difference in primary t/t success
between MtX (1mg/kg local & systemic) and Prostaglandin therapy
(OR1.0).
Systemix MtX in a single dose I.M regimen alone versus in combination
with oral mifeprestone
Gazvani 1998; Rozenberg 2003
 2 studies involving 262 women
 Single dose MtX significantly less successful compared to when oral
Mifeprestone 600mg was added. (OR 0.59).
 Persistent trophoblast occurred more frequently with single dose mtX only
(OR1.4)
 Study by Gazvani in 1998 showed e/o side effects in only 2 women in whole
study group.
 But study by Rozenberg in 2003 showed non significantly more side
effects (gastritis 30 vs 34, stomatitis 6 vs 8).
MtX Versus Hyperosmolar glucose via various different routes
 Non significant lower treatment success seen.
Sadan 2001; Gjelland 1995
EXPECTANT MANAGEMENT

Versus Systemic Methotrexate in low dose orally
(2.5mg/kg for 5 days).
Korhonen 1996
Double blind placebo controlled study in 60 women with serum
hCG levels <5000 IU/l.
 No significant differences were found in primary treatment
success (OR 1.0)
 23%of patients in both groups needed surgical interventions.
 No cause analysis & subsequent management detailed.


Versus Local & systemic prostaglandins
Small placebo controlled study in 23 patients with serum hCG
levels <2500 IU/l
Egarter 1991
 Expectant management was less successful than prostaglandins
therpay (OR 0.08)
 No side effects were reported.

WHAT’S BEST PRACTICE THEN?
35 RCTs studied 25 comparisons.
Surgical approach:






Reduced Costs with Lap Salpingostomy, when successful.
But Benefit of costs should be balanced against higher persistent
trophoblast rates in Lap. Group
If a laparatomy is still needed—minilap technique more feasible.
Prophylactic single dose MtX lowers the persistent trophoblast rate,
but NNT with MtX is 10:1—seriously undermining the usefulness of
this strategy.
Monitoring serum hCG seems better option.
Additional use of local vasopressin or oxytocin before surgery has no
impact on treatment success.
Conclusion:--Surgical approach with
technique is cost effective treatment.
laparoscopic
CONCLUSIONS: MEDICAL TREATMENT



Methotrexate widely studied drug.
Higher side effects rate prompted trial of Hyperosmolar
glucose / prostaglandins.
MtX vs these drugs, either alone or combination—no
significant differences found in treatment success or in side
effects. More so higher failure rates seen in Hyperosmolar glucose
use.

Local routes of MtX

Transvaginally –



Lap Guided—


needs direct visualisation, specific skills and expertise of the clinician
Less invasive & more effective compared to lap guided local MtX.
More invasive, carries risk of anaesthesia & trocar insertion—making lap surgery
the obvious choice.
Both modes significantly less effective than Lap salpingostomy.
MEDICAL TREATMENT CONTD.

Systemic MtX in fixed multiple doses:


No difference in short of long term medical outcomes compared to lap
salpingostomy
Health related QoL severely impaired in Mtx; but a C:C study indicated women
preference for non invasive management of tubal ectopic depsite higher treatment burden of systemic MtX
(Nieuwkerk 1998b)

But appears less expensive in women with initial serum hCG <1500.
Variable dose MtX—no significant difference compared to
surgical approach.
Conclusion:
 Medical treatment with fixed multiple or variable doses of
systemic MtX recommended in women with low inital serum
hCG concentrations.

Fixed Multiple doses regimen—1mg/kg MtX IM on d 0, 2,4,6 alternate with folinic acide 0.1mg/kg on D 1,3,5,7. 2nd course
given on day 14, if serum hCG on that day is 40% above inital value on day 0.
Variable dose regimen—single dose MtX 1mg/kg or 50mg/m2 additional MtX if serum hCG between D4 & D7 fails to
decline <15% of inital value on D1 given upto 3 doses week apart if needed. If hCG still fails to decline further—
surgical treatment.

Additional Criteria Suggested for using Systemic MtX
(ASRM 2006)

Pre-Treatment testing: Serum hCG, CBC, Liver & Renal
functions

Life Rules:







Patient compliance;
no use of alcohol, aspirin, NSAID’s or fol(in)ic acid supplements;
refrain from sexual intercourse;
avoidance of sunlight exposure;
fluid intake atleast 1.5l/day;
mouthwashes for stomatitis
Follow up:

Anti D i.m if Rh-ve
Pain relief measures
Serum hCG monitoring until undetectable
T/Vsonography

Delay of Pregnancy at least 3 months after treatment.



FINALLY ROLE OF EXPECTANT
MANAGEMENT

Both studies done so far—inadequate to identify
role of expectant modality as yet.
Low dose oral systemic MtX vs Placebo flawed at dose
used—unlikely to work
 Prostaglandins appeared more effective compared to
placebo alone (Trial was stopped pre-maturely)

DEFICIENCIES IN STUDIES

Methodological quality of 35 included studies was
poor
Only 53% studies specified randomisation process
 Only 32% studies specified allocation concealment


Many comparisons only had a single small scale
study


Small numbers inadequate to reliably compare different
outcome measures esp. Fertility outcomes.
Half of studies focussed only on short term
outcomes i.e. primary end point.

Secondary outcomes, including side effects, treatment
burden, costs and future fertility ignored, possibly due to
lack of effective long term follow up.
IMPLICATIONS FOR PRACTICE



Laparoscopic
treatment
Salpingostomy
cost
effective
Systemic Methotrexate is an alternative nonsurgical option, if diagnosis established non
invasively, thereby offering a complete noninvasive outpatient management.
Systemic MtX can only be recommended :
in hemodynamically stable women
 with an unruptured tubal ectopic
 and no signs of bleeding
 presenting with low serum hCG levels.

IMPLICATIONS FOR RESEARCH

Salpingostomy or Salpingectomy—still debatable

Fertility outcome measures still unclear in patients without
contralateral tubal pathologies.
Hajenius 1; Fernandez 2 trials ongoing to answer this query.

Medical treatment/expectant management
Reasearch needs focus on dosage schemes of systemic MtX
to improve efficacy, side effects profile , patient’s QoL &
cost.
 Role of expectant management in ectopic pregnancies with
low initial hCG levels(<1500).
Hajenius 2; Jurkovic et al trials ongoing
