BASICS
DESCRIPTION
Ectopic: pregnancy implanted outside the confines of the uterine cavity. Subtypes include:
- Tubal: pregnancy implanted in any portion of the fallopian tube
- Abdominal: pregnancy implanted intra-abdominally, most commonly after tubal abortion or rupture of tubal ectopic pregnancy
- Heterotopic: pregnancy implanted intrauterine and a separate pregnancy implanted outside uterine cavity
- Ovarian: implantation of pregnancy in ovarian tissue
- Cervical: implantation of pregnancy in cervix
- Intraligamentary: implantation of pregnancy within the broad ligament
EPIDEMIOLOGY
Incidence
- 108,800 cases in 1992 in the United States, according to CDC census (most recent data available) meaning that 1.5-2.0% of all pregnancies were ectopic. The true incidence is difficult to estimate because many patients are treated in the outpatient setting.
- In the United States, ectopic pregnancy is the leading cause of 1st-trimester maternal deaths and accounts for 6% of all pregnancy-related deaths.
- Heterotopic pregnancy, although rare (1:30,000), occurs with greater frequency in women undergoing in vitro fertilization (IVF) (1/1,000).
Prevalence
~33% recurrence rate if prior ectopic pregnancy
ETIOLOGY AND PATHOPHYSIOLOGY
- 97% of ectopic pregnancies occur in the fallopian tube, of which, 55% in the ampullary portion of the tube, 25% in the isthmus, and 17% in the fimbria.
- Of the remaining 3%, most are ovarian, cervical, abdominal pregnancies, or heterotopic.
- For a tubal pregnancy, impaired movement of the fertilized ovum to the uterine cavity due to dysfunction of the tubal cilia, scarring, or narrowing of the tubal lumen
- Other locations are rare but may occur from reimplantation of an aborted tubal pregnancy or from uterine structural abnormalities (mainly cervical pregnancy).
RISK FACTORS
- History of pelvic inflammatory disease (PID), endometritis, or current gonorrhea/chlamydia infection
- Previous ectopic pregnancy
- History of tubal surgery (~33% of pregnancies after tubal ligation will be ectopic)
- Pelvic adhesive disease (infection or prior surgery)
- Use of an intrauterine device (IUD): Overall chance of pregnancy of any type with an IUD is low; however, there is an increased likelihood of ectopic location if pregnancy occurs. IUDs reduce absolute risk of ectopic pregnancy.
- Use of assisted reproductive technologies
- Diethylstilbestrol exposure in utero (DES was last used in 1972)
- Tobacco use
- Patients with disorders that affect ciliary motility may be at increased risk (e.g., endometriosis, Kartagener).
GENERAL PREVENTION
- Reliable contraception or abstinence
- Screening and treatment of STIs (i.e., gonorrhea, chlamydia) that can cause PID and tubal scarring
DIAGNOSIS
HISTORY
In >50% of presenting cases, patients have sudden-onset abdominal pain coupled with cessation of/or irregular menses. Other common symptoms include nausea and/or vomiting, vaginal bleeding, and pain referred to the shoulder (from hemoperitoneum).
PHYSICAL EXAM
- Abdominal tenderness ± rebound tenderness
- Vaginal bleeding
- Palpable mass on pelvic exam (adnexal or cul-de-sac fullness)
- Cervical motion tenderness
- In cervical cases, an hourglass-shaped cervix might be noted.
- In cases of rupture and significant intraperitoneal bleeding, signs of shock such as pallor, tachycardia, and hypotension may be present.
DIFFERENTIAL DIAGNOSIS
- Missed, threatened, inevitable, or completed abortion
- Gestational trophoblastic neoplasia ("molar pregnancy")
- Appendicitis
- Salpingitis, PID
- Ruptured corpus luteum or hemorrhagic cyst
- Ovarian tumor, benign or malignant
- Ovarian torsion
- Cervical polyp, cancer, trauma, or cervicitis
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Human chorionic gonadotropin (hCG): Serial quantitative serum levels normally increase by at least 53% every 48 hours: Abnormal rise should prompt workup for gestational abnormalities. Clinical impression of acute abdomen/intraperitoneal bleeding concurrent with a positive hCG level is indicative of ectopic pregnancy until proven otherwise (1).
- CBC and ABO type and antibody screen
- Serum progesterone level (>20 mg/mL associated with lower risk of ectopic pregnancy). In women with pain and/or bleeding who have an inconclusive US, serum progesterone level <3.2 ng/mL ruled out a viable pregnancy in 99.2% of women (2).
- Under investigation: evaluation of serum progesterone levels in conjunction with vascular endothelial growth factor, inhibin A, and activin A using an algorithm. This diagnosed patients with ectopic pregnancy with 99% accuracy (3).
- Transvaginal US (TVUS) is the gold standard for diagnosis:
- Failure to visualize a normal intrauterine gestational sac when serum hCG is above the discriminatory level (>1,500 to 2,000 IU/L) suggests an abnormal pregnancy (4).
- Recent studies show an hCG level of 3,500 IU/L to be associated with a 99% probability of detecting a normal intrauterine gestational sac in clinical practice (5).
- These values are not valid for multiple gestations
- MRI is also useful but costly and rarely used if TVUS is available.
Diagnostic Procedures/Other
- In the setting of an undesired pregnancy, sampling of the uterine cavity with endometrial biopsy or D&C can identify the presence/absence of intrauterine chorionic villi. When an intrauterine pregnancy (IUP) has been evacuated by curettage, hCG levels should drop by 15% the next day (6).
- Historically, culdocentesis was performed to confirm suspected hemoperitoneum prior to surgical management. Currently, TVUS quantification of pelvic fluid is sufficient.
Test Interpretation
Products of conception (POC; especially chorionic villi) outside the uterine cavity
TREATMENT
MEDICATION
- Methotrexate (MTX): treatment for unruptured tubal pregnancy or for remaining POCs after laparoscopic salpingostomy. MTX inhibits DNA synthesis via folic acid antagonism by inactivating dihydrofolate reductase. Most effective when pregnancy is <3 cm diameter, hCG <5,000 mIU/mL, and no fetal heart movement is seen. Success rate is 88% if hCG <1,000 mIU/mL, 71% if hCG <2,000 mIU/mL:
- Dosage:
- Single: IM methotrexate: 50 mg/m2 of body surface area; may repeat once (preferred method) if <15% decline in hCG by day 7
- Double dose: methotrexate 50 mg/m2 of body surface area once and then repeated on day 4; if <15% decline in hCG on day 7, may repeat dose on days 7 and 11
- Multidose: methotrexate 1 mg/kg IM/IV every other day, with leucovorin 0.1 mg/kg IM in between. Maximum 4 doses; course may be repeated 7 days after last dose if necessary.
- Contraindications:
- Hemodynamic instability or any evidence of rupture
- Moderate to severe anemia
- Severe hepatic or renal dysfunction
- Immunodeficiency
- Relative contraindications
- Fetal heart rate seen
- Large gestational sac
- Noncompliance or limited access to hospital or transportation
- High hCG count >5,000 mIU/mL
- Precautions: immunologic, hematologic, renal, GI, hepatic, and pulmonary disease, or interacting medications
- Pretreatment testing: serum hCG, CBC, liver and renal function tests, blood type, and screen
- Patient counseling: During therapy, refrain from use of alcohol, aspirin, NSAIDs, and folate supplements (decreases efficacy of MTX); avoid excessive sun exposure.
- Adherence to scheduled follow-up appointments is critical.
- Increased abdominal pain may occur during treatment; however, severe pain, nausea, vomiting, bleeding, dizziness, or light-headedness may indicate treatment failure and require urgent evaluation.
- Rupture of ectopic pregnancy during MTX treatment ranges from 7% to 14%.
- Side effects include stomatitis, conjunctivitis, abdominal cramping, and rarely neutropenia, pneumonitis, or alopecia (7,8 and 9).
ISSUES FOR REFERRAL
- Consider gynecologic consultation if not experienced in medical management
- Refer to a gynecologist for surgical care.
ADDITIONAL THERAPIES
- Physician or patient may elect for surgical treatment as primary method, then postop hCG should guide need for MTX.
- After evidence of medical failure or tubal rupture, surgery is necessary.
- Surgery may either be salpingostomy (with preservation of tube) or salpingectomy (tubal removal). Abdominal entry is typically laparoscopic.
- Treatment of cervical, ovarian, abdominal, or other ectopic pregnancy is complicated and requires immediate specialist referral.
- Follow all patients treated medically to an hCG of 0 to ensure that there is no need for surgical intervention.
- Offer anti-D Rh prophylaxis at a dose of 50 μg to all Rh-negative women who have a surgical procedure to manage an ectopic pregnancy.
- Expectant management to allow for spontaneous resolution of ectopic pregnancy is acceptable in asymptomatic patients with no evidence of rupture or hemodynamic instability coupled with an appropriately low hCG (<200 mIU/mL) and no extrauterine mass suggestive of ectopic. Ruptured tubal pregnancies may occur even with extremely low hCG levels (<100 mIU/mL) (10).
SURGERY/OTHER PROCEDURES
- Indications include ruptured ectopic pregnancy, inability to comply with medical follow-up, previous tubal ligation, known tubal disease, current heterotopic pregnancy, desire for permanent sterilization at time of diagnosis.
- Laparoscopy is the first-line surgical management.
- Salpingostomy is preferred in patients who wish to maintain fertility particularly if contralateral tube is damaged/absent:
- No difference in recurrence rate compared to salpingectomy (11).
- Persistent trophoblastic tissue with salpingostomy remains in the fallopian tube in 4-15% of cases.
- Salpingectomy is indicated for uncontrolled bleeding, recurrent ectopic pregnancy, severely damaged tube, large gestational sac, or patient desire for sterilization.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Fails criteria for methotrexate management, suspicion of rupture, orthostatic, shock, and severe abdominal pain requiring IV narcotics
- Inpatient observation in the setting of an uncertain diagnosis, particularly with an unreliable patient, may be appropriate.
- Surgical emergency
- Two IV access lines should be placed immediately if suspicion of rupture; aggressive resuscitation as needed
- Blood product transfusion if necessary en route to OR
- In cases of shock, pressors and cardiac support may be necessary.
IV Fluids
- Unnecessary for a stable ectopic pregnancy being medically treated
- Critical for a surgical patient who is bleeding
Nursing
Strict input/output, hourly vitals, orthostatics if mobile, frequent abdominal exams, serial hematocrit, pad counts if heavy vaginal bleeding
Discharge Criteria
Afebrile, abdominal pain resolving or resolved, diagnosis established, surgical treatment, and recovery is complete
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Serial serum quantitative hCG until level drops to zero:
- After methotrexate administration, a strict monitoring protocol should be followed (8).
- Following salpingostomy, weekly levels are appropriate.
- Following salpingectomy, further follow-up may be unnecessary.
- Pelvic US for persistent or recurrent masses
- Pain control: brief course of narcotics usually necessary
- Liver and renal function tests following methotrexate administration if repeat dosing is required
- Delay of subsequent pregnancy for at least 3 months after treatment with methotrexate due to teratogenicity (folate deficiency)
DIET
- During treatment, avoid foods and vitamins high in folate (leafy greens, liver, edamame) due to interaction with methotrexate efficacy.
- Maintain excellent hydration.
PATIENT EDUCATION
- Signs and symptoms of ectopic pregnancy should be reviewed.
- Patients should be encouraged to plan subsequent pregnancies and seek early medical care on discovery of future pregnancies.
PROGNOSIS
- Chronic ectopic pregnancies are rare and treated with surgical removal of the fallopian tube.
- Future fertility depends on fertility prior to ectopic pregnancy and degree of tubal compromise.
- ~66% of women with a history of ectopic pregnancy will have a future IUP if they are able to conceive.
- If infertility persists beyond 12 months, the fallopian tubes should be evaluated.
COMPLICATIONS
- Hemorrhage and hypovolemic shock
- Persistent trophoblastic tissue after medical or surgical management
- Infection
- Infertility
- Blood transfusions with associated infections/transfusion reaction
- Disseminated intravascular coagulation in the setting of massive hemorrhage
REFERENCES
11 Barnhart KT, Sammel MD, Rinaudo PF, et al. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol. 2004;104(1):50-55.22 Verhaegen J, Gallos ID, van Mello NM, et al. Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-analysis of cohort studies. BMJ. 2012;345:e6077.33 Rausch ME, Sammel MD, Takacs P, et al. Development of a multiple marker test for ectopic pregnancy. Obstet Gynecol. 2011;117(3):573-582.44 Barnhart K, Mennuti MT, Benjamin I, et al. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol. 1994;84(6):1010-1015.55 Connolly A, Ryan DH, Stuebe AM, et al. Reevaluation of discriminatory and threshold levels for serum β-hCG in early pregnancy. Obstet Gynecol. 2013;121(1):65-70.66 Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol. 2006;107(2 Pt 1):399-413.77 Bachman EA, Barnhart K. Medical management of ectopic pregnancy: a comparison of regimens. Clin Obstet Gynecol. 2012;55(2):440-447.88 Practice Committee of the American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy. Fertil Steril. 2006;86(5 Suppl 1):S96-S102.99 Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril. 2007;87(3):481-484.1010 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 94: medical management of ectopic pregnancy. Obstet Gynecol. 2008;111(6):1479-1485.1111 Mol F, van Mello NM, Strandell A, et al. Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial. Lancet. 2014;383(9927):1483-1489.
ADDITIONAL READING
- Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med. 2009;361(4):379-387.
- Hajenius PJ, Mol F, Mol BW, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev. 2007;(1):CD000324.
- National Institute for Clinical Excellence. Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management in Early Pregnancy of Ectopic Pregnancy and Miscarriage. London, United Kingdom: National Institute for Clinical Excellence, 2012.
- Sagiv R, Debby A, Feit H, et al. The optimal cutoff level of human chorionic gonadotropin for efficacy of methotrexate treatment in women with extrauterine pregnancy. Int J Gynaecol Obstet. 2012:116(2):101-104.
CODES
ICD10
- O00.9 Ectopic pregnancy, unspecified
- O00.1 Tubal pregnancy
- O00.0 Abdominal pregnancy
- O00.2 Ovarian pregnancy
- O00.8 Other ectopic pregnancy
ICD9
- 633.90 Unspecified ectopic pregnancy without intrauterine pregnancy
- 633.10 Tubal pregnancy without intrauterine pregnancy
- 633.00 Abdominal pregnancy without intrauterine pregnancy
- 633.20 Ovarian pregnancy without intrauterine pregnancy
- 633.80 Other ectopic pregnancy without intrauterine pregnancy
SNOMED
- 34801009 Ectopic pregnancy (disorder)
- 79586000 tubal pregnancy (disorder)
- 82661006 Abdominal pregnancy
- 9899009 ovarian pregnancy (disorder)
- 17433009 ruptured ectopic pregnancy (disorder)
CLINICAL PEARLS
- Ectopic pregnancy is the leading cause of 1st-trimester maternal death and accounts for 6% of U.S. pregnancy deaths.
- 97% of ectopic pregnancies occur in the fallopian tube.
- Diagnosis requires high clinical suspicion in the setting of abdominal pain and a positive pregnancy test.