ECTOPIC PREGNANCY; MEDICAL MANAGEMENT

DR. ANTHONY WANJALAMOI UNIVERSITY SCHOOL OF MEDICINE

ELDORET KENYA

5TH DEC 2012

o What are the predictors of Success?

o What are the available options?

o Is multi-dose methotrexate superior to single-dose?

o 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?

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)

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)

Fetal cardiac activityo 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)

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.

Other Contra-Indications

o Immuno-deficiencyo Peptic Ulcer diseaseo Active Pulmonary diseaseo Known sensitivity to methotrexateo Alcoholism, Alcoholic liver disease or other chronic

liver diseaseo Preexisting blood dyscrasias, such as bone marrow

hypoplasia, leukopenia, thrombocytopenia, or significant anemia

(ACOG practice bulletin number 94, June 2008)

Available options

o Methotrexate

o Methotrexate + Mifepristone

o Hyperosmolar Glucose

Methotrexate

o Folic acid antagonist.

o Competitively inhibits the binding of dihydrofolic acid to dihydrofolate reductase thus ↓ folinicacid……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.

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 -hCGundetectable

Weekly until serum -hCGundetectable

Weekly until serum -hCGundetectable

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.

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).

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

o Following methotrexate administration, up to half of women experience a short duration of abdominal pain that can be controlled with nonsteroidal anti-inflammatory 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.

Mifepristone Plus Methotrexate

o In a randomized trial of 212 cases, Rozenbergand co-workers (2003) documented no differences in success rates.

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 intragestationalinjection (Fernandez, 1994).

Hyperosmolar Glucose

o In a small prospective trial, Yeko and colleagues (1995) reported that direct injection of 50-percent 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.

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).

Medical versus Surgical Therapy

o Hajenius and colleagues compared a multidosemethotrexate protocol with laparoscopic salpingostomy and found no differences for tubal preservation and primary treatment success (Hajenius, 1997).

o Health-related quality of life—pain, posttherapydepression, 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

• 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).

Expectant Management

o Distinguishing patients who are experiencimgsponteneous 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]

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.

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

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

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.