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? 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

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

salpingostomya. 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 salpingostomya. 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)

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

19/35 trials described method of allocation & all 35 stated occurrence of randomisation

Allocation concealment 11/35 studies described concealed allocation

Blinding 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.

RESULTSLaproscopic Salpingostomy versus Open Salpingostomy 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

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 Ugur 1996

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 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 TREATMENTSystemix 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. 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

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

Criteria used in studies were: 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: 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 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 mifeprestoneGazvani 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/lEgarter 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 laparoscopic technique is cost effective treatment.

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 –

needs direct visualisation, specific skills and expertise of the clinician Less invasive & more effective compared to lap guided local MtX.

Lap Guided— 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 Salpingostomy cost effective treatment

Systemic Methotrexate is an alternative non-surgical option, if diagnosis established non invasively, thereby offering a complete non-invasive 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