Tubal pregnancy

OVERVIEW: What every practitioner needs to know

Ectopic pregnancy is an urgent obstetrical complication that should be considered when a reproductive-aged female presents with any combination of amenorrhea, vaginal bleeding, and pelvic pain.

It is important to remember that one cannot rely on symptoms and physical findings alone to rule out ectopic pregnancy. The clinical presentation may be nonspecific; and the same symptoms occur more commonly with spontaneous abortion and even normal pregnancy.

Early ectopic diagnosis in the adolescent age group relies on a thorough and confidential sexual history that leads to specific evaluation for pregnancy. Initial evaluation includes obtaining a last menstrual period (LMP), last date of sexual activity (especially unprotected sexual activity), and urine pregnancy testing. If there are concerns about ectopic pregnancy based on symptoms, then transvaginal ultrasound (TV-US) and serial beta human chorionic gonadotropin (b-hCG) levels should be performed. Discordance between the LMP, TV-US, and b-hCG should alert providers to possible ectopic and further evaluation.

Absence of a normal gestational sac in the uterus, with an LMP estimated at 5 weeks or greater and a b-hCG of 2000 mIU/ml or more, is concerning for abnormal pregnancy. Abnormal elevations in b-hCG, including an increase of less than 53% over 48 hours, is suggestive of a nonviable pregnancy, including ectopic.

There are a variety of medical and surgical therapeutic options that are equivalent in overall tubal health, risk of future ectopic pregnancies, and fertility that may be available to the patient depending on patient and pregnancy characteristics (Level A recommendation).

Are you sure your patient has a tubal pregnancy? What are the typical findings for this disease?

• The most common symptoms

Ectopic pregnancies may present with a “classic triad” of symptoms; however, many ectopic patients do not present with this triad, or this triad is also present in patients with normal pregnancy or spontaneous abortion.

Clinicians should have a low threshold for suspecting pregnancy in adolescent females presenting with these or other vague abdominal complaints:

• abdominal or pelvic pain

• vaginal bleeding

• amenorrhea

TIPS

• Symptoms and physical exam findings can be nonspecific

  The triad of symptoms occurs more commonly with spontaneous abortion

  Cannot rely on symptoms or exam findings alone to rule out ectopic

• Early diagnosis of ectopic in adolescents relies on:

  A thorough and confidential sexual history including:

  LMP

  Ever sexually active

  Last unprotected sexual activity

  Urine pregnancy test

Definitions

Ectopic pregnancy is any pregnancy outside the uterine cavity. Tubal pregnancies account for 97% of all ectopics (55% ampulla, 25% isthmus, 17% fimbria). The remaining 3% are located in the ovary, cervix, abdomen, or uterine cornua.

What other disease/condition shares some of these symptoms?

Below are some common sources of acute pelvic pain in the adolescent that require urgent diagnosis:

(See Table I. Creating a Differential for the Adolescent with Acute and Chronic Pelvic Pain)

Gynecologic: Pregnancy-related, so may also have amenorrhea and/or vaginal bleeding

Normal pregnancy

Spontaneous abortion

Molar pregnancy

Post-abortion endometritis

Gynecologic: Non-pregnancy-related

Pelvic inflammatory disease

Tubo-ovarian abscess

Ovarian torsion

Ovarian cyst rupture

Hemorrhagic or ruptured corpus luteum

Non-Gynecologic

Acute appendicitis

Pyelonephritis

Renal stone

What caused this disease to develop at this time?

Commonly cited risk factors (in order of highest strength of association) for ectopic pregnancy may include:

• Prior ectopic pregnancy

• Previous tubal surgery, including tubal ligation

• In utero diethylstilbestrol exposure

• Chlamydia

• History of pelvic inflammatory disease or other genital infections

• Infertility

• Assisted reproductive technologies

• Current tobacco use

• Current IUD in place

Contraceptive use reduces the risk of both intrauterine and ectopic pregnancy. However, if conception occurs with an intrauterine device in place or previous tubal ligation surgery, it is more likely to be an ectopic pregnancy.

The risk of recurrent ectopic pregnancy is around 10% whether or not medical or surgical treatment is employed.

Using the History and Exam to assess risk of ectopic pregnancy

History indicative of an ectopic pregnancy may include the classic triad of amenorrhea, abdominal pain, and vaginal bleeding. However, up to 30% of patients with ectopic pregnancy have no vaginal bleeding.

Exam findings related to ectopic presentation include: pelvic/abdominal tenderness (90%), vaginal bleeding (70%), and adnexal mass (10%). Of note, 10% have a normal pelvic exam. Peritoneal signs such as guarding and rebound tenderness in combination with hypotension suggest ruptured ectopic pregnancy.

Because no combination of history and physical exam findings can reliably exclude ectopic pregnancy, it is important to move to laboratory studies and imaging in women with an unlocated pregnancy.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Pregnancy testing is the initial step when reproductive age women present with abdominal pain, vaginal bleeding, or amenorrhea.

Urine hCG

• Home tests for urine human chorionic gonadotropin (u-hCG) are positive at 50-100 mIU/ml

• Professional tests for u-hCG are positive at 20-50 mIU/ml

• There are low sensitivity urine h-CG tests that are positive at levels closer to 1500-2000 mIU/ml

Serial quantitative serum b-hCG

Serum quantitative beta-human chorionic gonadotropin (b-hCG) can be positive at levels as low as 5 mIU/ml. B-hCG tests are most useful when done in conjunction with transvaginal ultrasound (TV-US). Discriminatory zones are expected correlations between b-hCG with TV-US findings typical for normal pregnancy. Intrauterine pregnancy with yolk sac or embryo on ultrasound effectively rules out ectopic pregnancy with the rare exception of heterotopic pregnancy (1/4000). (see below in imaging section and Table II. Evaluation of Normal and Abnormal Pregnancy Using b-hCG and Ultrasound.) Comparing changes in b-hCG levels allows clinicians to predict normal and abnormal pregnancy based on expected increases in normal pregnancies over standard periods of time. The most rapid rise in b-hCG is prior to 10,000 mIU/ml and then slows to a peak of 100, 000 mIU/ml around 10 weeks of gestation.

If the b-hCG level is below the discriminatory zone and the TV-US is nondiagnostic, serial b-hCG levels should be followed. The minimum b-hCG rise for a potentially viable pregnancy in a patient with symptoms of pain and/or vaginal bleeding is 53% in 48 hours. If a woman is clinically stable with an initial nondiagnostic ultrasound and an appropriately increasing b-hCG level, TV-US should be repeated when the b-hCG reaches the discriminatory zone. A b-hCG increase of <53% in 48 hours suggests abnormal pregnancy, either ectopic or failed intrauterine pregnancy. Abnormal rises in b-hCG only have 36% sensitivity and 65% specificity for detecting ectopic pregnancy. This is because ectopic pregnancies can have normally rising b-hCG levels 21% of the time. Therefore, it is important to consider the results of TV-US as well both initially and when the b-hCG levels reach the discriminatory zone.

Declining b-hCG levels suggest abnormal pregnancy, usually a nonviable intrauterine pregnancy, but b-hCG levels can fall like a spontaneous abortion 8% of the time. If the initial b-hCG is < 200 miU/ml, almost 90% of women experience spontaneous abortion that requires no medical or surgical intervention. However, it is important to follow b-hCG levels down to undetectable levels until ectopic pregnancy is ruled out.

Progesterone

Progesterone generally remains constant during the first trimester and is not specific to gestational age like b-hCG values. However, it can be an adjunct in evaluating normal and abnormal pregnancy. Levels less than 5 ng/ml are 100% specific for abnormal pregnancy. Values greater than 20-25 ng/ml have a 100% positive predictive value for normal pregnancy. Many values remain in the indeterminate range (5-20 ng/ml) and are not particularly useful in determining a clear diagnosis. Progesterone in the evaluation of ectopic pregnancy is a test of low sensitivity (15%) as the large number of indeterminate levels are less useful for diagnostic purposes. Therefore, progesterone measurements are not routinely used in the work-up of ectopic pregnancy.

Additional diagnostic and pre-treatment labs may also include:

• CBC with differential (in anticipation of methotrexate treatment and to evaluate degree of bleeding)

• Blood group and Rh(D) typing (to determine whether Rhogam is needed)

• Liver function tests (in anticipation of methotrexate treatment)

• Renal function tests (in anticipation of methotrexate treatment)

(See Table III. Assessing Diagnostic Testing for Ectopic Pregnancy)

TIPS

• A single quantitative b-hCG is not useful in ruling out ectopic pregnancy because both ruptured and unruptured ectopics can occur in ranges <100 mIU/ml

• Serial quantitative b-hCG values in conjunction with TV-US are the most effective testing combination.

Would imaging studies be helpful? If so, which ones?

Pelvic ultrasound is the diagnostic test of choice, especially useful in conjunction with b-hCG levels. Initial evaluation can use a single b-hCG level to assist in interpreting US findings by creating expected “discriminatory levels” for normal pregnancy. (See Table II. Evaluation of Normal and Abnormal Pregnancy Using b-hCG and Ultrasound.)

Discriminatory levels or zones are expected normal intrauterine contents at particular b-hCG values. The discriminatory level should be set by each institution according to the equipment used and expertise of the sonographers. Transabdominal US should show an intrauterine gestational sac if b-hCG is >6,500 mIU/ml. TV-US should show an intrauterine gestational sac if b-hCG is >1,500-2000 mIU/ml, the estimated value at 4.5-5 wk EGA (estimated gestational age).

Other TV-US findings in normal pregnancy may include: yolk sac at a mean gestational sac diameter of 6-8 mm, or 5 wk EGA by LMP; fetal pole at a mean gestational sac diameter of 5-12mm or 5-6wk EGA by LMP, fetal heart beat at a mean gestational sac diameter of 13-18 mm and crown rump length of 5 mm, or 6-6.5 wk EGA by LMP. TV-US findings suggestive of abnormal intrauterine pregnancy include: a gestational sac > 10 mm without presence of a yolk sac; a gestational sac > 20 mm with no fetal pole, and absence of fetal heart beat with fetal pole > 5 mm. It is important to remember that multiple gestations have higher b-hCG levels than singletons at any gestational age. In these cases, b-hCG levels may be > 2000 mIU/ml before pregnancy is detected on ultrasound.

An intrauterine gestational sac associated with a normal pregnancy can be confused with a pseudosac of ectopic pregnancy. A pseudosac can form within the uterine cavity due to bleeding from the decidualized endometrium. A pseudosac is located centrally in the uterus, filling the uterine cavity. This is in contrast to a true intrauterine gestational sac of normal pregnancy, which has the following characteristics: a double ring sign indicative of a decidual reaction and implantation; location at the fundus; eccentric placement off midline stripe indicative of implantation.

Other TV-US findings that are abnormal and suggestive of ectopic include an adnexal mass and fluid in the pouch of Douglas. An ectopic pregnancy can also be diagnosed by TV-US when a clear gestational sac with fetal pole or yolk sac is visualized in the adnexa.

Uterine Evacuation

If the pregnancy is determined to be nonviable by serial b-hCG, TV-US, or progesterone testing, and/or the pregnancy is not intended or unwanted by the patient, uterine evacuation offers a diagnostic means of evaluating the location of the pregnancy by visualization of the uterine cavity contents.

Uterine evacuation via dilation and curettage with either manual or electric suction for an unwanted or abnormal intrauterine pregnancy demonstrates typical products of conception (POCs), including villi and gestational sac. POCs can be viewed by floating uterine contents in a clear pyrex dish and a light box. Blood, along with an absence of gestational sac and villi, are concerning for pseudosac and ectopic pregnancy. Microscopic evaluation for chorionic villi should also be obtained because it is more accurate than floating tissue in early or failed gestations.

If microscopic evaluation is not available immediately, b-hCG levels can be checked 12-24 hours after uterine evacuation. If the level does not drop significantly (at least by 15%), then ectopic pregnancy is diagnosed. Again, it is critical that suction curettage as a diagnostic procedure only be offered if the pregnancy is grossly abnormal/non-viable and/or patient is not intending to continue the pregnancy. This is never done in a diagnostic capacity for a desired potentially continuing pregnancy.

Confirming the diagnosis

See above discussions regarding use of history, physical exam, labs and imaging to assess for ectopic pregnancy.

(See Figure 1. Algorithm: Assessment, Diagnosis and Management of Ectopic Pregnancy; and Figure 2. Diagnostic Algorithm for Ectopic Pregnancy)

Figure 2

TIPS

Comparing EGA with LMP, TV-US ,and serial changes in b-hCGs is an initial effective methodology for early diagnosis of ectopic pregnancy.

A positive urine pregnancy test with an empty uterus may indicate early normal pregnancy, early pregnancy failure, or ectopic pregnancy.

The presence of an intrauterine yolk sac and/or fetal heart activity is 100% predictive of a viable intrauterine pregnancy.

This effectively rules out ectopic pregnancy, with the exception of heterotopic twin pregnancy, which is rare (1/4000).

Assisted reproductive technology increases the risk of heterotopic twin pregnancy to 1/100.

A rise in serum bhCG of less than 53% in 48 hrs most likely indicates an abnormal pregnancy.

If no intrauterine pregnancy is visualized above the discriminatory cutoff, consideration should be given to uterine evacuation in order to differentiate between spontaneous abortion and ectopic pregnancy.

If you are able to confirm that the patient has a tubal pregnancy, what treatment should be initiated?

(Please see Figure 1. Algorithm: Assessment, Diagnosis and Management of Ectopic Pregnancy; and

Figure 2. Diagnostic Algorithm for Ectopic Pregnancy)

If the patient is hemodynamically unstable with suspected or known ectopic pregnancy, priorities include:

• Support hemodynamically with oxygen, cardiorespiratory monitor, NPO, IV access, IV fluids, type and cross for possible transfusion

• Consult obstetrics-gynecology for urgent surgical evaluation

If the patient is hemodynamically stable with known ectopic pregnancy, there are 3 potential management pathways: expectant, medical, and surgical.

Expectant management

Expectant management is an option for early ectopic pregnancy in a reliable, stable patient. While current studies are not adequate to make strong recommendations based on evidence, the following characteristics can be helpful in determining who may be followed carefully with expectant management:

• Hemodynamically stable

• Asymptomatic

• b-hCG <1,000 mIU/ml and decreasing

• TV-US adnexal mass measures < 3 cm diameter

• TV-US adnexal mass with no fetal heart beat

• Patient reliability and adherence assured, with access to medical care

Most patients with very low initial b-hCGs (<200 mIU/ml) will resolve spontaneously. While expectant management is less likely to be effective than medical or surgical intervention, some early ectopic pregnancies can resolve without intervention. Women must be counseled about the potential risks of tubal rupture and hemorrhage and b-hCG levels must be followed serially until undetectable. If women experience increased pain, failure of b-hCG levels to decline, or tubal rupture, then alternative treatment must be initiated. This strategy should not be undertaken without the advice of an obstetrician-gynecologist.

Medical management with methotrexate

Medical management can be offered in situations when patients meet the following criteria:

• Hemodynamically stable

• Patient reliability and adherence assured, with access to medical care

• Unruptured mass

Contraindications to medical management are just as important as indications and include:

• Hemodynamic instability

• Severe persistent pain

• Evidence of active bleeding (hemoperitoneum)

• Renal failure (cr >1.5 mg/dl)

  Impaired renal clearance risks significant toxicity (bone marrow suppression, acute respiratory distress syndrome, bowel ischemia); dialysis not improve clearance

• Active pulmonary disease

• Hepatitis or liver disease (LFTs > 2x normal)

• Preexisting blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia

• Breastfeeding

• Heterotopic viable twin pregnancy

• Immunodeficiency

• Peptic ulcer disease

Relative contraindications to medical management:

• Gestational sac larger than 3.5cm

• Embryonic cardiac motion

Medical methods for ectopic management use methotrexate (MTX), which competitively inhibits dihydrofolate reductase, blocking the synthesis of DNA, RNA, thymidylates, and proteins, and so is cytotoxic to the rapidly dividing cells of a pregnancy. Because MTX affects rapidly dividing cells, it can also affect the bone marrow, gastrointestinal mucosa, and respiratory epithelium. Therefore, side effects of MTX can include nausea, vomiting, stomatitis, rash, alopecia, elevation of liver enzymes, and bone marrow suppression. However, with the doses used for ectopic pregnancy, the most common side effects are nausea, vomiting, and stomatitis. When using MTX, it is important to avoid: nonsteroidal anti-inflammatory and folic acid medications; alcohol, sexual intercourse, strenuous activity, and exercise.

Overall success rates for medical management are 71.2% to 94.2%. Success rates depend on the treatment regimen used, gestational age, and b-hCG level. Single dose MTX therapy is associated with a higher failure rate (14.3%) when pretreatment b-hCG levels are greater than 5,000 mIU/ml compared to a 3.7% failure rate when b-hCG levels are less than 5,000 mIU/ml. Whichever MTX regimen is used, b-hCG levels must be followed weekly until undetectable. Ectopic pregnancies can rupture even when b-hCG levels are declining. Side effects are no different between the MTX regimens, once adjusted for pretreatment b-hCG levels.

MTX single-dose therapy is most efficacious when b-hCG is < 5000 mIU/ml. It is an intramuscular injection (IM) and dosed by body surface area (BSA) at 50 mg/meter². MTX is given on day 1. Serial b-HCGs are measured on day 4 and 7 and a drop of at least 15% should be expected. B-hCG levels are then measured weekly until undetectable. If there is a less than 15% decrease between day 4 and 7, repeat the dose of MTX and repeat b-hCG measurements on days 4 and 7.

MTX two-dose therapy involves MTX (50mg/m² IM) on day 0 and again on day 4. Similar to single-dose therapy, b-hCG levels are checked on days 4 and 7, and there should be at least a 15% drop. If the decrease is 15% or more, measure b-HCG levels weekly until undetectable. If the decrease is less than 15%, readminister MTX 50 mg/m² on days 7 and 11 and follow b-hCG levels as before. The two-dose regimen is a compromise between the single-dose and multiple-dose regimen, and in some centers is used for b-hCG levels >1,000 mIU/mL.

MTX multiple dose regimen is more useful for ectopic pregnancy with higher pretreatment b-hCG levels (>5000 mIU/mL) and in women with more advanced gestations including embryonic cardiac activity. MTX is given IM at a dose of 1 mg/kg on days 1,3,5,7. It is alternated with folic acid (leucovorin) 0.1 mg/kg on days 2,4,6,8. B-hCG levels are measured on MTX dose days and continue until levels have decreased by at least 15% from the previous measurement. If the decrease is 15% or more, measure b-HCG levels weekly until undetectable. Repeat CBC, LFTs, and serum creatinine one week after the last dose of MTX.

Surgical management

Surgical management is indicated when patients are actively bleeding, hemodynamically unstable, for more advanced gestations with embryonic cardiac activity, when there are contraindications to methotrexate, or for patient preference or inability to comply with medical treatment protocols.

Laparoscopy with salpingostomy (removal of trophoblastic tissue only) or salpingectomy (removal of fallopian tube with the implanted trophoblastic tissue) is the preferred approach.

Laparotomy is generally used for cases where active intraperitoneal bleeding is extensive and hypovolemic shock must be rapidly prevented. Intraabdominal adhesions may also prevent the use of laparoscopy.

Laparoscopic salpingostomy has a failure rate of 3%-20%, but this can be mitigated with post-operative monitoring of b-hCG levels and administration of MTX as needed. There is no definitive data that salpingostomy, as opposed to salpingectomy, is associated with better fertility outcomes. Similarly, there are conflicting studies as to whether salpingostomy is associated with a higher recurrent ectopic pregnancy rate than salpingectomy. The decision to perform salpingostomy compared with salpingectomy is often made intraoperatively, depending on how damaged the tube appears.

At present, using current guidelines, there do not appear to be any differences between surgical management and medical management with respect to long-term outcomes such as future fertility or recurrent ectopic pregnancy.

Additional therapeutic considerations

If Rh(D) negative, give anti Rh(D) immune globulin (Rhogam) 50 mcg IM.

Longer term treatment and follow-up include serial bhCGs (daily to weekly) until levels are undetectable, which indicates resolution of pregnancy with no retained POCs. Treatment failure is defined when levels do not decline as expected. Additional MTX doses or MTX administered postoperatively may provide some benefit. If levels rise or there is continued bleeding or pain, surgical evaluation is required. Pelvic pain is common and expected 2-3 days after a course of MTX and should be followed by close observation. If the patient is hemodynamically stable and the pain is mild, she can be managed expectantly.

Signs of treatment failure and/or tubal rupture include significantly worsening abdominal pain, hemodynamic instability, levels of b-hCG that do not decline by at least 15% between day 4 and day 7 post-injection, and increasing or plateauing of the b-hCG levels after the first week of treatment.

(Please see Table IV. Ectopic Pregnancy Treatment Options)

What are the adverse effects associated with each treatment option?

Expectant management carries the risk of tubal rupture and intraperitoneal bleeding.

MTX affects rapidly dividing tissues such as bone marrow, gastrointestinal lining, and respiratory epithelium. It is contraindicated in patients with blood dyscrasias, and severe and active gastrointestinal and respiratory diseases. MTX is cytotoxic to hepatocytes and cleared by renal excretion, so is also contraindicated in significant liver or kidney disease. Side effects and adverse outcomes are dose and treatment duration dependent. The most common side effects include: abdominal pain, nausea, vomiting, and stomatitis. Abdominal pain is common 2 to 3 days after dosing due to MTX’s effect on trophoblastic tissue. Additional side effects may include: rash, increased LFTs, bone marrow suppression, or alopecia. A rise in LFTs can be seen with multidose regimens. MTX side effects resolve with discontinuation of therapy or are minimized with rescue doses of leucovorin. Restriction of the use of alcohol and nonsteroidal anti-inflammatory drugs (NSAIDs) is also recommended.

Surgical management is a more invasive procedure with longer recovery times but fewer systemic side effects. The risks of surgery include: anesthesia risks, bleeding, infection, injury to internal organs, adhesion formation, and, with salpingostomy, risk of persistent ectopic pregnancy.

At present, there appears to be no differences between surgical or medical treatment in terms of future intrauterine pregnancies or recurrent ectopic pregnancies.

What causes this disease and how frequent is it?

Most epidemiologic data is from the 1980’s to 1990’s, with the total number of ectopic pregnancies in the United States at just over 100,000 (108,800; 95% CI=83,600-134,000; rate: 19.7 per 1000 reported pregnancies). This represented an increase from 0.5% of pregnancies in 1970 to 2% in the early 1990’s. As most women with ectopic pregnancy are now managed in the outpatient setting, current estimates of ectopic pregnancy in the United States are lacking.

Since 1987 (coincident with managing ectopic pregnancies in the outpatient setting), there have been decreases in mortality—due to improved diagnosis of early ectopic pregnancy with serum beta- human chorionic gonadotropin (b-hCG) testing and transvaginal ultrasound (TV-US) and decreases in resultant infertility– due to early diagnosis and medical management options with methotrexate.

While uncommon, ectopic pregnancy is still the major cause of mortality in first-trimester pregnancy, and accounts for up to 9% of all pregnancy-related deaths in the United States. The current estimated rate for heterotopic twin pregnancy is 1 in 4,000.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can tubal pregnancy be prevented?

Prevention Includes behavioral factors — see risk factors re STI/PID, fertility treatment, smoking

What is the evidence?

“Medical management of ectopic pregnancy. ACOG Practice Bulletin No. 94”. Obstet Gynecol. vol. 111. 2008. pp. 1479-85. (Guidelines offered by ACOG with levels of evidence for recommendations.)

“Medical management of ectopic pregnancy”. (Guidelines offered by ARHQ with levels of evidence based on ACOG 2008 evidence and recommendations.)

Della-Giustina, D, Denny, M. “Ectopic pregnancy”. Emerg Med Clin N Am. vol. 21. 2003. pp. 565-84. (Overview of emergency medicine approach to ectopic diagnosis from 2003.)

Deutchman, M, Tubay, AT, Tukok, D. “First trimester bleeding”. Am Fam Physician. vol. 79. 2009. pp. 985-94. (Overview of normal and abnormal pregnancies presenting with first trimester bleeding. Provides key clinical recommendations with level of evidence.)

Eyvazzadeh, AD, Levine, D. “Imaging of pelvic pain in the first trimester of pregnancy”. Radiol Clin North Am. vol. 44. 2006. pp. 863-77. (Gives classic ultrasound images and discussion of interpretation in the light of pregnancy and pelvic pain.)

Hajenius, PJ, Mol, BW, Bossuyt, PM. “Interventions for tubal ectopic pregnancy”. Cochrane Database Syst Rev. 2007. (Cochrane review for tubal ectopic pregnancy interventions and outcomes. Analysis of 35 studies with 25 different comparisons. General conclusion is that laparoscopic treatment is most cost effective in surgical approaches and that medical management should be considered as an excellent additional option in selected patients. They could not evaluate efficacy and outcomes of expectant management based on their criteria.)

Lozeau, AM, Potter, B. “Diagnosis and management of ectopic pregnancy”. Am Fam Physician. vol. 72. 2005. pp. 1707-14. (Good general overview of ectopic care with evidence ratings, algorithms, and references.)

Menon, S, Colins, J, Barnhart, KT. “Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review”. Fertil Steril. vol. 87. 2007. pp. 481-4. (Systematic review of 5 observational studies regarding success of methotrexate medical management of ectopic pregnancy. Summary analysis concludes that single dose methotrexate is less likely to work with bhcg levels > 5000 mIU/ml.)

Mol, F, Mol, BW, Ankum, WM. “Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis”. Hum Reprod Update. vol. 14. 2008. pp. 309-19. (Systematic review of RCT from 1966 until 2007. Detailed and specific recommendations with longstanding and recent references. Also, compares cost effectiveness.)

“Medical treatment of ectopic pregnancy”. Fertil Steril. vol. 90. 2008. pp. S206-212.

Seeber, BE, Barnhart, KT. “Suspected ectopic pregnancy”. Obstet Gynecol. vol. 107. 2006. pp. 399-413. (Clinical expert series from Obstetrics and Gynecology. Provides the latest information on how to diagnose and manage ectopic pregnancy based on Dr. Barnhart's work defining B-hCG curves.)

Van Mello, NM, Mol, F, Mol, BW, Hajenius, PJ. “Conservative management of tubal ectopic pregnancy”. Best Pract Res Clin Obstet Gynaecol. vol. 23. 2009. pp. 509-18.

Ongoing controversies regarding etiology, diagnosis, treatment

There needs to be much more data/evidence to determine efficacy of expectant management.

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