Department of Clinical Epidemiology University of Santo Tomas Faculty of Medicine and Surgery

Department of Clinical EpidemiologyUniversity of Santo Tomas

Faculty of Medicine and Surgery

Case 6: Ectopic Pregnancy

Lazaro, D. to Lim, PatrickGroup 1 – 3C

Clinical Decision on a DIAGNOSTIC TEST

Case Scenario

• A.T. 25 yo female G3P1 (1-0-1-1) admitted because of vaginal spotting. She has a positive pregnancy test a week ago and a menstrual delay of 15 days. Last July 2006, she had the same complaint and passage of grape like tissue for which D & C was done. PPE: RR=30/min, mild tenderness at right iliac & hypogastrium; Cervix is soft and slightly tender, bluish with brownish discharge from the os. There is mild tenderness of the slightly enlarged uterus and of the right adnexa area.

Salient Features• 25-year old, female, G3P1 (1-0-1-1) • Vaginal spotting• (+) Pregnancy test• Menstrual delay of 15 days• RR = 30/min• Mild tenderness at the right iliac & hypogastrium• Cervix: soft and slightly tender, bluish with

brownish discharge from os• Mild tenderness of the slightly enlarge uterus

and of the right adnexa area.

Differential Diagnosis• Molar Pregnancy

• Trophoblastic disease – persistent trophoblast

• Normal Pregnancy

• Salpingitis

• Corpus luteum cysts

• Adnexal torsion

• Appendicitis

Symptoms Percentage of Patients with Symptoms

Abdominal pain 90 – 100

Amenorrhea 75 – 95

Vaginal bleeding 50 – 80

Dizziness, fainting 20 – 35

Urge to defecate 5 – 15

Pregnancy symptoms 10 – 25

Passage of tissue 5 - 10

From Weckstein, LN: Current perspective on ectopic pregnancy. Obstet Gynecol Surv 40:259, 1985.

Table 1. Symptoms of Ectopic Pregnancy

Signs Percentage of Patients with Sign

Adnexal tenderness 75 – 90

Abdominal tenderness 80 – 95

Adnexal mass 50

Uterine enlargement 20 – 30

Orthostatic changes 10 – 15

Fever 5 – 10

From Weckstein, LN: Current perspective on ectopic pregnancy. Obstet Gynecol Surv 40:259, 1985.

Table 2. Signs of Ectopic Pregnancy

Clinical Question

What is the most accurate diagnostic tool in a reproductive age female presenting with signs & symptoms of ectopic pregnancy?

Population: Reproductive female, positive pregnancy test, menstrual delay

Intervention: Diagnostic testOutcome: Accuracy

Search Terms:Reproductive age female, diagnostic

procedure, ectopic pregnancy

Limits: Added to PubMed in the last 10 years,

Published in the last 10 years, Humans, Female, All Adult: 19+ years

Search Strategies

PubMed Basic Search Keywords: positive pregnancy test, menstrual delay, tenderness at right adnexa & hypogastrium

PubMed Clinical Queries

Advance Search:Category – Diagnosis

Scope – broad & sensitive

Keywords: reproductive age women AND diagnostic tool AND ectopic pregnancy

Articles Found and Appraised

1. George Condous, Emeka Okaro, Asma Khalid, Chuan Lu, Sabine Van Huffel, D Timmerman, Tom Bourne. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy. Human Reproduciton Vol. 20, No.5 pp. 1404 – 1409, 2005.

2. Jun Y, Naobumi Y, Takahiro K, Toshihiro O, Hajime K. (2006). Diagnosis of ectopic pregnancy with MRI: efficacy of T2*-weighted imaging. Magnetic Resonance in Medical Sciences, Vol. 5, No.1, pp. 25-32

3. Refaat Bassem, Amer Saad, Ola Bolarinde, Chapman Neil, Ledger William. The expression of Activin- βA and –βB -Subunits, Follistatin, and Activin Type II Receptors in Fallopian Tubes Bearing an Ectopic Pregnancy. The Journal of Clinical Endocrinology Metabolism Vol 93, No. pp. 293-299, 2008

4. Pasquale Florio, Filiberto Maria Severi, caterina Bocchi, Stefano Luisi, Massimo Mazzini, Secondo Danero, Michela Torricelli, Felice Petraglia. Single Serum Activin A Testing to Predict Ectopic Pregnancy. The Journal of Clinical Epidemiology and Metabolism Vol 92, No.5 pp. 1748 – 1753, 2007.

Evidence Based MedicineEvidence Based Medicine: DIAGNOSIS: DIAGNOSIS

Spectrum of Disease: Ectopic Pregnancy

20% 80%

65%

Critical Appraisal

VALIDITY:

Was there an independent, blind comparison with a reference standard?

All women who presented in the Early Pregnancy Unit (EPU) underwent TVS and other data obtained (i.e. levels HCG & progesterone) were available after TVS was done & therefore did not influence the ultrasonographer.

The reference standard used was laparoscopy/laparotomy histologic exam, which was only performed in patients who were suspected to have ectopic pregnancy on TVS. To those with negative TVS results, the reference standard was not applied and the “true” results of these cases were obtained through a follow up. However the study did not provide the result of the follow up, and so the group performed a sensitivity analysis to determine the study’s sensitivity & specificity.


Critical AppraisalWas the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom we should use it in practice? )

Yes. The scans were performed for a multitude of symptoms and the patients presented themselves in the EPU at varying AOG during their first trimester.

Was the reference standard applied regardless of the diagnostic test result?

No. As mentioned, the study did not employ the gold standard in patients with intra-uterine pregnancy on TVS. On the 200 patients diagnosed to have EP on TVS, histologic confirmation was done in only 152 managed surgically. 48/200 were managed conservatively hence no confirmatory histology obtained surgically could be done.

VALIDITY:

Was the test validated in a second independent group of patients?

No, the tests were not validated in a second, independent group of patients

Were the methods for performing the test describe in sufficient detail to permit replication?

Yes, the study performed TVS using a 5MHz probe and the criteria used to diagnose EP were enumerated in the study (Materials & Methods, p. 1405, col 1, par 1)

Sensitivity Analysis

Total Number of Patients: 6621

TVS

Pregnancy of Unknown

Location (PUL): 581

Intrauterine Pregnancy (IUP): 5840

Ectopic Pregnancy (EP)*: 200

*Fulfilled criteria set by the study for diagnosis of EP on TVS

Surgically managed:

152

Conservative management:

48

(-): 9 (+): 143

FN TN

FP TP

Sensitivity Analysis

• Best Case Scenario– If the 48 patients managed conservatively

were considered to have positive results on gold standard, then

TP = 143 + 48 = 191

• Worst Case Scenario– If the 48 patients managed conservatively

were considered to have negative results on gold standard, then

FP = 9 + 48 = 57

BEST CASE + -

+ 191 9

- 581 5840TVS

Gold standard: Laparoscopy

Specificity: 100%Sensitivity: 25%LR (-): 0.75LR (+): 160.79PTP (-): 58%PTP: (+): 100%

WORST CASE + -

+ 143 57

- 581 5840

Specificity: 99%Sensitivity: 20%LR (-): 0.81LR (+): 20.3PTP (-): 60%PTP (+): 97%

Gold standard: Laparoscopy

TVS

CLINICAL IMPORTANCE:

What is the sensitivity? 20-25%

What is the specificity? 99-100%

Can you calculate the likelihood ratio or is there one already calculated?

Yes


APPLICABILITY:

In our practice, is the test available? Affordable? Accurate?

Yes, TVS is available in the Philippines.In USTH, TVS costs P975 & P315 in the private & charity ward respectively.

Can we generate a reasonablepre-test probability in ourclinical scenario?

Yes since the most common signs and symptoms of ectopic pregnancy are present in our patient.

Are the study patients similar toour own?Has anything changed since thestudy was published?

Yes, the study is similar since the study subjects are women suspected to have ectopic pregnancy who are in the same age group as our patient. No, nothing has changed since the study was published.

APPLICABILITY:

Will the resultant post-test probability change out management?

Post test probability if TVS is (+): 99-100%Post test probability if TVS is (-): 58-60% Since the post test probability for a positive result did not fall within the testing zone, no further diagnostic tools are needed if the test is positive.

On the other hand, if the result is negative, further diagnostic work-ups are needed.

Spectrum of Disease: Ectopic Pregnancy

20% 80%

65%

TVS Post-test ProbabilityLower/Upper Testing ThresholdPretest Probability

58- 60%

99 - 100%

Comment• Transvaginal ultrasound, when positive,

can be diagnostic for ectopic pregnancy in reproductive age group females presenting with signs and symptoms of vaginal spotting, delayed menstruation, positive pregnancy test, and tenderness at right iliac and hypogastric area. However, a negative result would need further diagnostic work-ups.


THERAPY

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Clinical Scenario Question: What is the best surgical method to

treat ectopic pregnancy?

- In terms of less blood loss, operating time, hospital stay

(recovery period), injection pain relief and complications.

Population Women in the reproductive age, w/ ectopic pregnancy

Comparative

Intervention

Minilaparotomy

Outcome Treatment (blood loss, operating time, hospital stay

(recovery period), injection pain relief and complications)

Method Randomized Control Trial

Search

Terms:

Surgery, ectopic pregnancy, treatment26

Articles Found and Appraised1. A RANDOMIZED CONTROLED COMPARISON OF MINILAPAROTOMY AND LAPAROTOMY IN

ECTOPIC PREGNANCY CASES

27

Journal Title:A RANDOMIZED CONTROLED COMPARISON OF MINILAPAROTOMY AND LAPAROTOMY IN

ECTOPIC PREGNANCY CASES

J B SHARMA, S GUPTA, M MALHATORA, R ARORA;Indian Journal of Medical Science Vol 57 No 11 November 2003

28

Relevance

• The study aimed to compare the efficacy and safety of minilaparotomy surgery for ectopic pregnancy cases with standard laparotomy method.– Population – women in reproductive age (19-40 yrs. Old) with

suspected ectopic pregnancy– Intervention – Surgery: Minilaparotomy– Outcome – safety and less complications– Methodology – Randomized Control trial (computer generated

numbers)

29

VALIDITY:Was the assignment of patients to treatment

randomized?

• The assignment of patients to treatment was randomized

using computer generated numbers.

• This is seen in the TITLE, ABSTRACT and METHODOLOGY

30

Were all patients who entered the trial properly accounted for and attributed at its conclusion?

• Yes. All patients (60 cases) were accounted for. • In Tables 2 and 3 analysis, the sum of the patients

totaled the number who were randomized at the start of the study.

Was Follow-up complete?• Patients were discharged if there were no complications and

were seen in the outpatient clinic after 2 weeks for any complications and to collect their histopathology report (Methodology)

31

•Patients were analyzed in the groups to which they were randomized. Conversion of surgical method was not done (Results)

•No drop-outs and withdrawals.

•0 cases of readmissions and repeat laparotomy

32

Were the patients analyzed in the groups to which they are randomized?

• Yes, there was no crossing over in the study groups

Were the patients, health workers and study personnel blind to treatment?

• No blinding - surgical in nature– Blinding was not mentioned in the paper

Were the groups similar at the start of the treatment?• - Yes. Table 1 of the results section showed no significant difference in

the baseline characteristics between the two groups.33

RESULTS

09/04/09

• Complication rates (Table 3)

35

Complications Group 1 (n=30) Group 2 (n=30) Stat sig.

% %

Paralytic ileus 3 10.0 8 26.66 P 0.45

Urinary retention

1 3.33 4 13.33 P 0.44

Fever 4 13.33 6 20.0 P 0.45

UTI 2 6.66 3 10.0 ns

Wound Infection

1 3.33 5 16.66 0.45

Malaria 1 3.33 0 0.0 ns

Readmission 0 0.0 0 0.0 ns

Repeat Laparotomy

0 0.0 0 0.0 ns

Total 12 25

09/04/09

RC

(DC/NC)

8/ 30 26.6%

RT

(DT/NT)

3 / 30 10.0%

RR

(RT/RC)

.10/.27 0.37 or

37%

RRR

(1-RR)

1-0.37 .63 or

63%

ARR

(RC-RT)

26.6-10% 16.6%

or .17

NNT

(1/ARR)

1/.17 5.88

Paralytic ileus

RC

(DC/NC)

4/ 30 13.3%

RT

(DT/NT)

1/ 30 3.3%

RR

(RT/RC)

.03/.13 .23 or

23%

RRR

(1-RR)

1-0.23 .77 or

77%

ARR

(RC-RT)

13.3-3.3% 10%

or .10

NNT

(1/ARR)

1/.10 10

Urinary retention

09/04/09

Fever

RC

(DC/NC)

6/ 30 0.2 or 20%

RT

(DT/NT)

4/ 30 0.13 or 13.3%

RR

(RT/RC)

0.13/0.2 .65 0r 65%

RRR

(1-RR)

1-0.65 0.35 or 35%

ARR

(RC-RT)

.20-0.13 .07 or 7%

NNT

(1/ARR)

1/.07 14.29

RC

(DC/NC)

3/ 30 .10 or 10%

RT

(DT/NT)

2/ 30 .0667 or 6.67%

RR

(RT/RC)

.067/.10 .67 or 67%

RRR

(1-RR)

1-.67 .33 or 33%

ARR

(RC-RT)

.10-.067 .33 or 33%

NNT

(1/ARR)

1/.33 3.03

UTI

09/04/09

Wound Infection

RC

(DC/NC)

5/ 30 16.67%

RT

(DT/NT)

1 / 30 3.33%

RR

(RT/RC)

.03/.17 .18 or

18%

RRR

(1-RR)

1- 0.18 .82 or 82%

ARR

(RC-RT).17-.03 .14 or

14%

NNT

(1/ARR)1/ .14 7.14

RC

(DC/NC)

0/ 30 0%

RT

(DT/NT)

1 / 30 3.33%

RR

(RT/RC)

RRR

(1-RR)

ARR

(RC-RT)

NNT

(1/ARR)

Malaria – dko lam if ksama pa tong malaria na ito!

RC

(DC/NC)

25 / 30 83.3%

RT

(DT/NT)

12 / 30 40.0%

RR

(RT/RC)

.40/ .833 0.48

RRR

(1-RR)

1 – 0.48 0.52 or 52%

ARR

(RC-RT)

83.3-40.0 43.3% or .43

NNT

(1/ARR)

1 / 0.43 2.33

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RESULTS: total complications

p value = 0.05 Confidence interval = 95%

09/04/09

Table 2. Other endpoints measured

Table 2. See results on operating time

Table 3. See results on Hospital stay

Pain relief

CARING FOR MY PATIENT:Can the results be applied to my patient care?

• Inclusion criteria– reproductive aged

women w/ mean age of the Tx Group at 25 yrs. old

– Ectopic pregnancy

41

•Exclusion criteria▫Patients w/ significant

medical dse like diabetes, hypertension and previous laparotomy

Were all clinically important outcomes considered? Outcome, results

• 0 reported deaths• 0 readmission• 0 repeat laparotomy

• The main outcomes considered were the development of complications

• Paralytic ileus, urinary retention, fever, UTI, wound infection, malaria

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Bottomline

• Conclusion– Surgery by minilaparotomy technique in ectopic

pregnancy cases appears to be a safe and feasible method and is superior to conventional laparotomy as there are minimum postoperative complications and patients can be discharged early w/o the need of expensive equipment.

– There is also less estimated blood loss, operating time, hospital day stay , pain relief injections needed.

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Clinical Decision on HARM

Clinical Question

What are the complications of performing surgical treatment

(salpingectomy) in women with ectopic pregnancy?

• Population: women with ectopic pregnancy• Intervention: salpingectomy• Outcome: risks, harm, complications• Method: cohort

• Search Terms: ectopic pregnancy, laparoscopy, laparotomy complications

• Limits: full text article, within the last 10 years

Articles AppraisedChan, C.C.W., Ng, E.H.Y., Li, C.F. and Ho, P.C., Impaired Ovarian Blood Flow and Reduced Antral Follicle Count following Laparoscopic Salpingectomy for Ectopic Pregnancy, Human Reproduction, 2003.

• Zhu L., Wong, F., Bai J., Operative Laparotomy vs Laparoscopy for the Management of Ectopic Pregnancy, Chinese Medical Journal, 2000.

Relevance

Is the objective of the article on harm similar to your clinical dilemma?

Yes. The objective of the study is to compare the ovarian function of the operated side with the non-operated side after unilateral salpingectomy performed through laparoscopy or laparotomy for ectopic pregnancy.

Validity

Did the investigator assemble clearly defined groups of patients similar in all important ways other than exposure?

Yes. Inclusion criteria were set by the investigators. They included patients with history of unilateral salpingectomy for treatment of ectopic pregnancy at least 3 months ago, no history of ovarian or tubal surgery, no extensive pelvic adhesions found during the operation, no ovarian cyst on pelvic ultrasound scan exam and no hormonal treatment for the preceding 3 months.

Materials and Methods, p 2177

The baseline characteristics of the population of the study were also noted.

Table III p.2178

Validity

Were exposures and outcomes measured in the same ways in both groups (objective/blinded)?

Yes, the exposures and outcomes were measured similarly. 3D ultrasound scan examinations were performed by CCWC using Voluson 730. Assessors were blinded to the treatment the patients received. Antral follicle count obtained using same machine in 2D mode. Both ovaries were scanned.

Material and Methods , p2177

Validity

Was follow up sufficiently long and complete?

The outcome was assessed at least 3 months post-salpingectomy.

The interval from operation to ultrasound examination of the laparoscopy group was 7 months while in the laparotomy group was 38 months.

Table III p 2178

Validity

Is it clear that the causation preceded the onset of the outcome?

Yes, part of the inclusion criteria is that the patient has undergone unilateral salpingectomy of at least 3 months prior.

Materials and Methods p 2177

During the imaging procedure of all women, the outcome indices of the operated side (unilateral salphingectomy site) were compared to that of the unoperated side

Is there a dose response relationship?

There is no dose response relationship since the main operation done to the women was surgical, not medical.

Do the results of the harm study fulfill some of the tests for causation?

ValidityIs the association consistent across studies?

Yes, the exposures and outcomes were measured similarly. 3D ultrasound scan examinations were performed by CCWC using Voluson 730. Assessors were blinded to the treatment the patients received. Antral follicle count obtained using same machine in 2D mode. Both ovaries were scanned.

Material and Methods , page 2177

ValidityDoes the association have biological plausibility?

Yes. In laparoscopic salpingectomy, bipolar diathermy was the method employed in cauterizing the mesosalphinx which may have led to a more extensive damage not limited to the excision site. Impaired ovarian blood flow may have resulted to a disruption in the blood supply.

Discussion page 2178

Applicability

What other treatments are available?

Other treatments available would be an open salpingotomy or linear salpingotomy. Use of conservative management could also be employed. Medical management single or multiple dose methotrexate could also be utilized. However, in catholic institutions, the procedure of choice due to ethical considerations is salphingectomy. Other centers may offer salphingotomy or medical management.

Conclusion

• There was a significant reduction in antral follicle count and ovarian blood flow in the laparoscopy group.

• However, the laparotomy group had significantly longer interval between the operation and assessment.

• Longer interval between the time of operation and assessment in the laparoscopy group is recommended to rule out the possibility that the reduction in antral follicle count and ovarian blood flow is short-term.

Prognosis

Comments by the doctors are “italicized”

57

Search Question

• What’s the fertility rate after surgical treatment for ectopic pregnancy?

• Search terms:– Prognosis, fertility, ectopic pregnancy, surgery– Fertility, tubal pregnancy, surgery,

salpingectomy– Fertility, tubal pregnancy, surgery, radical,

conservative58

• Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study.

• Bouyer J, Job-Spira N, Pouly JL, Coste J, Germain E, Fernandez H.

• INSERM U292, Bicêtre Hospital, Le Kremlin-Bicêtre, France.

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Critical Appraisal

Relevance:

Is the objective of the article on prognosis similar to your clinical dilemma?

Yes, one of the objectives of the study is to compare the fertility rates of radical, conservative-surgical or medical treatments (page 714, Objective)

Was there a representative sample of patients without the outcome at the start of observation?

291 cases of confirmed ectopic pregnancy & attempted to conceive again (Page 714, sample)

Was follow-up sufficiently long and complete?

Yes, they followed up the women every 6 months until the age of 45 years old(Page 715, Methods)

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Critical AppraisalRelevance:

Is the objective of the article on prognosis similar to your clinical dilemma?

Yes, one of the objectives of the study is to compare the fertility rates of radical, conservative-surgical or medical treatments (page 714, Objective)

Was there a representative sample of patients without the outcome at the start of observation?

291 cases of confirmed ectopic pregnancy & attempted to conceive again (Page 714, sample)



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Critical AppraisalRelevance:

Were the criteria for determining the prognostic factor and outcome explicit and credible?

Yes, to determine reproductive outcomesRecurrence of ectopic pregnancySpontaneous intrauterine pregnancy

For both cases survival analysis methods were used.

A trained investigator was in charge for collecting data from each woman: sociodemographic characteristics, sexual, gynecological, reporductive & surgical histories, conditions of conception etc.

(page 715, Data analysis)

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Clinical AppraisalRelevance:

Was there adjustment for other prognostic factors?

Yes, univariate analysis & cox regression were used to take into account confounding variables

(Page 716, data analysis)

Overall is the study valid?

Yes, all the validity questions were answered



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Results

• How large is the likelihood of outcome to occur in those with the prognostic factor in a specified period of time? Was it statistically significant?

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Recurrent Ectopic Pregnancy

Initial Treatment

# of women # of recurrent EP

2-yr cumulative rate of recurrent EP

P*

Radical 100 10 (10%) 0.27 (0.12;0.55)

0.55

Conservative-surgical

166 17 (10%) 0.25 (0.14; 0.42)

Medical 25 3 (12%) 0.41 (0.14; 0.85)

Total 291 30 0.27 (0.17; 0.41)

* P value of the log rank test between the 3 treatments

Table 3. Recurrent ectopic pregnancy according to the initial treatment. Values are given as n or rate (95% CI), unless otherwise indicated

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There’s no significant difference with regards to recurrence of ectopic pregnancy in between the 3 treatments.

Crude Cumulative rates of spontaneous intrauterine

pregnancy

Fig 1. Crude cumultive rates of spontaneous intrauterine pregnancy according to initial treatment for EP (page 718, figure 1) 67

Crudely:Medical appears superior, followed by conservative surgical then radical being the lowest.

ResultsConservative (salpingostomy)

Radical(salpingectomy)

Medical(methotrexate , IM)

Statistical significance P>0.05

Cumulative rates of Intrauterine pregnancy (18mos)

73%(95% CI 65-80%)

57%(95% CI 44-70%)

80%(95% CI 60-95%)

Not significant

Recurrent ectopic

10% (17/166) 10% (10/100) 12% (3/25) Not significant

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But after the multivariate analysis, there’s no significance in the cumulative rates of intrauterine pregnancy between the 3 treatments. PS: In the table above, the data encoded are crude, but the entry for statistical significance is after multivariate analysis

Hazard ratio: In this study, the reference used was the conservative surgical because it’s the procedure mostly used by doctors. In computing for hazard ratio, the data in conservative was used as a denominator. For example in page 718, table 4, if hazard ratio of medical is 1.2, then it means that there’s a 1.2 more risk for medical compared to conservative-radical.

Clinical AppraisalApplicability

Are the study patients similar to my own?

Yes, study patients are 15-44 y/o who had ectopic (tubal pregnancy)Our patient is 25 y/o who also has ectopic pregnancy

(Page 715 methods)Can I use the results to decide the intervention or reassure my patient?

Yes, the study concluded that there was no significant difference in recurrent ectopic pregnancy & cumulative rates of Intrauterine pregnancy between the treatments

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Resolution of the Problem in the Scenario

• According to the study, there’s no significant difference between the treatments with regards to preserving fertility & recurrence of ectopic pregnancy

• Salpingectomy will be recommended to the patient.

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In UST, if the baby is dead, both salphingostomy & salpingectomy is ethical & allowed. Although salpingostomy is more often used since it’s easier & has a shorter hospital stay. However if the baby is still alive then, salpingectomy is the only treatment that’s ethical

Department of Clinical Epidemiology University of Santo Tomas Faculty of Medicine and Surgery

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