Gestational trophoblastic disease

Ectopic pregnancy is a high-risk condition that occurs in 1.9 percent of reported pregnancies. The condition is the leading cause of pregnancy-related death in the first trimester. If a woman of reproductive age presents with abdominal pain, vaginal bleeding, syncope, or hypotension, the physician should perform a pregnancy test. If the patient is pregnant, the physician should perform a work-up to detect possible ectopic or ruptured ectopic pregnancy. Prompt ultrasound evaluation is key in diagnosing ectopic pregnancy. Equivocal ultrasound results should be combined with quantitative beta subunit of human chorionic gonadotropin levels. If a patient has a beta subunit of human chorionic gonadotropin level of 1,500 mIU per mL or greater, but the transvaginal ultrasonography does not show an intrauterine gestational sac, ectopic pregnancy should be suspected. Diagnostic uterine curettage may be appropriate in patients who are hemodynamically stable and whose beta subunit of human chorionic gonadotropin levels are not increasing as expected. Appropriate treatment for patients with nonruptured ectopic pregnancy may include expectant management, medical management with methotrexate, or surgery. Expectant management is appropriate only when beta subunit of human chorionic gonadotropin levels are low and declining. Initial levels determine the success of medical treatment. Surgical treatment is appropriate if ruptured ectopic pregnancy is suspected and if the patient is hemodynamically unstable.

Ectopic pregnancy is any pregnancy that occurs outside the uterine cavity. Pregnancies in the fallopian tube account for 97 percent of ectopic pregnancies: 55 percent in the ampulla; 25 percent in the isthmus; 17 percent in the fimbria; and 3 percent in the abdominal cavity, ovary, and cervix. (1)

The rate of ectopic pregnancies in North America climbed from less than 0.5 percent of all pregnancies in 1970 to 2 percent in 1992. (1-3) Ruptured ectopic pregnancy accounts for 10 to 15 percent of all maternal deaths. (1,2) Fortunately, after the advent of transvaginal ultrasonography and beta subunit of human chorionic gonadotropin (beta-hCG) tests, the incidence of rupture and case-fatality rates declined from 35.5 deaths per 10,000 ectopic pregnancies in 1970 to 3.8 per 10,000 in 1989. (2) Management options for ectopic pregnancy include expectant management, medical treatment, and surgery.

Risk Factors

Risk factors most strongly associated with ectopic pregnancy include previous ectopic pregnancy, tubal surgery, and in utero diethylstilbestrol (DES) exposure. A history of genital infections or infertility and current smoking increase risk. (3,4) Contraceptive use reduces the annual risk for intrauterine and ectopic pregnancy (5,6); however, previous intrauterine device use may increase risk. Table 1 lists common risk factors for ectopic pregnancy. (4,5)

Diagnosis

Ectopic pregnancy is most common in women of reproductive age who present with abdominal pain and vaginal bleeding approximately seven weeks after amenorrhea. (1,2,7) These findings are nonspecific and are common in patients who may miscarry. (1) Table 2 lists the common differential diagnosis of ectopic pregnancy.

CLINICAL EXAMINATION

A normal or slightly enlarged uterus, vaginal bleeding, pelvic pain with manipulation of the cervix, and a palpable adnexal mass significantly increase the likelihood of an ectopic pregnancy. Significant abdominal tenderness suggests ruptured ectopic pregnancy, especially in a patient with hypotension who presents with guarding and rebound tenderness.

Physicians can categorize hemodynamically stable patients as high, intermediate, or low risk for ectopic pregnancy (Table 3 (7,8)) based on clinical examination findings. (7) Clinical examinations are not diagnostic because up to 30 percent of patients with ectopic pregnancies have no vaginal bleeding, 10 percent have a palpable adnexal mass, and up to 10 percent have negative pelvic examinations. (1,7) The overall likelihood of ectopic pregnancy is 39 percent in a patient with abdominal pain and vaginal bleeding but no other risk factors. (9) The probability of ectopic pregnancy increases to 54 percent if the patient has other risk factors (e.g., history of tubal surgery, ectopic pregnancy, or pelvic inflammatory disease; in utero DES exposure; or an intrauterine device in situ at the time of conception). (9) Physicians should remember that no combination of physical examination findings can reliably exclude ectopic pregnancy. (1,10-13)

DIAGNOSTIC TESTS

Diagnostic tests for ectopic pregnancy include a urine pregnancy test; ultrasonography; beta-hCG measurement; and, occasionally, diagnostic curettage. In the past, some physicians have used serum progesterone levels as well. (2,14) Table 4 summarizes the accuracy rates of diagnostic tests for ectopic pregnancy. (1,14-17)

Ultrasonography is the diagnostic test of choice, with limitations largely based on availability and the gestational age of the pregnancy. (3,14,18) Ectopic pregnancy is suspected if transabdominal ultrasonography does not show an intrauterine gestational sac and the than 6,500 mIU per mL (6,500 IU per L) or if transvaginal ultrasonography does not show an intrauterine gestational sac and the mIU per mL (1,500 IU per L) or greater. (2,19) Ultrasound findings that suggest ectopic pregnancy are listed in Table 5. (9) More than one half of women with ectopic pregnancy have beta-hCG levels less than 2,000 mIU per mL (2,000 IU per L) at presentation. Therefore, it may be difficult to determine by ultrasonography alone whether an empty uterus indicates early pregnancy or ectopic pregnancy. (2,7)

Beta-hCG levels may assist in interpreting ultrasound findings. In a normal intrauterine pregnancy, these levels would increase by at least 53 percent every two days, peaking at a level greater than 100,000 mIU per mL (100,000 IU per L). (1,20) Beta-hCG levels alone cannot differentiate between ectopic and intrauterine pregnancy, and serial beta-hCG levels that do not increase appropriately in a woman with suspected ectopic pregnancy are only 36 percent sensitive and approximately 65 percent specific for detection of ectopic pregnancy. (14,15) It also is important to note that ruptured and unruptured ectopic pregnancies have been identified at beta-hCG levels less than 100 mIU per mL (100 IU per L) and greater than 50,000 mIU per mL (50,000 IU per L). (1)

Serum progesterone levels can detect pregnancy failure and identify patients at risk for ectopic pregnancy, but they are not diagnostic of ectopic pregnancy. Sensitivity for diagnosis of ectopic pregnancy is very low (15 percent); therefore, 85 percent of patients with ectopic pregnancy will have normal serum progesterone levels. (9) Algorithms for diagnosing ectopic pregnancy that include progesterone levels miss more ectopic pregnancies and require more surgeries than do algorithms without progesterone. (9,10,14,16,17)

Diagnostic uterine curettage may detect chorionic villi. If chorionic villi are not detected, ectopic pregnancy should be suspected. Curettage should only be considered when beta-hCG levels are falling or when levels are elevated and ultrasonography does not show intrauterine pregnancy. (2,14) Diagnostic uterine curettage could terminate a desired pregnancy.

RECOMMENDED DIAGNOSTIC STRATEGY

The American College of Emergency Physicians and the American College of Obstetricians and Gynecologists have issued guidelines for using ultrasonography and beta-hCG levels to evaluate patients with suspected ectopic pregnancy. (14,15) Figures 1 and 2 are algorithms based on these guidelines. (1,14,15,17,20)

[FIGURES 1-2 OMITTED]

When evaluating patients for suspected ectopic pregnancy, physicians should take a history and perform a physical examination; then they should determine the (Table 3 (7,8)) and order transvaginal ultrasonography. (10,18) If a low-risk patient's ultrasonography is negative for intrauterine pregnancy, and she is hemodynamically stable and has a beta-hCG level less than 1,500 mIU per mL, the physician should take another beta-hCG measurement after 48 hours. Patients with a nondiagnostic transvaginal ultrasonography result and a beta-hCG level of 1,500 mIU per mL or greater are at an increased risk for ectopic pregnancy and may need a surgical consultation or uterine evacuation procedure. If a patient's condition is unstable, immediate surgical consultation is needed, and a uterine evacuation procedure may be considered. If chorionic villi are absent, ectopic pregnancy is likely.

Combined transvaginal ultrasonography and serial quantitative beta-hCG measurements are approximately 96 percent sensitive and 97 percent specific for diagnosing ectopic pregnancy. Therefore, transvaginal ultrasonography followed by quantitative beta-hCG testing is the optimal and most cost-effective strategy for diagnosing ectopic pregnancy. (9,10,21)

Treatment

EXPECTANT MANAGEMENT

Expectant management is between 47 and 82 percent effective in managing ectopic pregnancy. (22,23) A good candidate for expectant management has a beta-hCG level less than 1,000 mIU per mL (1,000 IU per L) and declining, an ectopic mass less than 3 cm, no fetal heartbeat, and has agreed to comply with follow-up requirements.

MEDICAL TREATMENT

Methotrexate, a folic acid antagonist, is a well-studied medical therapy. Methotrexate deactivates dihydrofolate reductase, which reduces tetrahydrofolate levels (a cofactor for deoxyribonucleic acid and ribonucleic acid synthesis), thereby disrupting rapidly-dividing trophoblastic cells. (24) Other therapeutic agents include hyperosmolar glucose, prostaglandins, and mifepristone (Mifeprex). (24)

Protocols for methotrexate therapy include single-dose and multiple-dose regimens (Table 6 (24)). Although no studies have compared the protocols, the single-dose regimen is easier to administer and is used more often. In a 2003 meta-analysis (24) of methotrexate therapies, 20 studies examined the single-dose regimen, and six examined the multiple-dose regimen. The single-dose regimen created fewer side effects but was slightly less effective, with a crude overall success rate of 88 percent compared with the multiple-dose regimen's 93 percent success rate. Methotrexate, regardless of the protocol, had an overall 89 percent crude success rate. (24) Side effects of methotrexate include bone marrow suppression, elevated liver enzymes, rash, alopecia, stomatitis, nausea, and diarrhea. The time to resolution of the ectopic pregnancy is three to seven weeks after methotrexate therapy.

Patient selection is important in the medical management of ectopic pregnancy. The lower the beta-hCG levels at initiation of treatment, the higher the success rate of methotrexate therapy (Table 7). (26) In addition to having a beta-hCG level less than 15,000 mIU per mL (15,000 IU per L), a candidate for medical treatment must be reliable and able to follow-up daily if necessary. (15) Surgical management may be considered if a patient does not meet these criteria. Women with certain medical conditions (e.g., liver disease with a transaminase level two times greater than normal, renal disease with a creatinine level greater than 1.5 mg per dL [133 [micro]mol per L], immune compromise with a white blood cell count less than 1,500 per [mm.sup.3] [1.5 x [10.sup.9] per L] and platelets less than 100,000 x [10.sup.3] per [mm.sup.3] [100 x [10.sup.9] per L], significant pulmonary disease) are not candidates for methotrexate. (27)

Patients treated with methotrexate have been shown to have the same quality of life after methotrexate treatment compared with patients who had surgical treatment. Women experienced more pain, had less energy, and had worse health perception during the first few weeks after treatment with methotrexate, but they had the same quality of life after 16 weeks. (28)

SURGICAL TREATMENT

Before the advent of laparoscopy, laparotomy with salpingectomy (removal of the fallopian tube through an abdominal incision) was the standard therapy for managing ectopic pregnancy. Laparoscopy with salpin-gostomy, without fallopian tube removal, has become the preferred method of surgical treatment. Laparoscopy has similar tubal patency and future fertility rates as medical treatment. (25) Salpingostomy has an estimated 8 to 9 percent failure rate, which can be managed with methotrexate.

Follow-Up and Prognosis

During treatment, physicians should examine patients at least weekly and sometimes daily. Serial beta-hCG measurements should be taken after treatment until the level is undetectable. If the levels fail to decline, the patient can be treated with a second course of methotrexate or with methotrexate post-surgery. Surgical intervention is necessary if beta-hCG levels increase.

The prognosis is good for patients who receive appropriate treatment. With proper patient selection, success rates approach 82 percent for expectant management, 90 percent for medical management, and 92 percent for surgical management. (22,23,26)

FUTURE FERTILITYAND RISK OF RECURRENCE

Approximately 30 percent of women treated for ectopic pregnancy later have difficulty conceiving. The overall conception rate is approximately 77 percent regardless of treatment. (3) Rates of recurrent ectopic pregnancy are between 5 and 20 percent, but the risk increases to 32 percent in women who have had two consecutive ectopic pregnancies. (2,3)

Author disclosure: Nothing to disclose.

REFERENCES

(1.) Della-Giustina D, Denny M. Ectopic pregnancy. Emerg Med Clin North Am 2003;21:565-84.

(2.) Tenore JL. Ectopic pregnancy. Am Fam Physician 2000;61:1080-8.

(3.) Tay JI, Moore J, Walker JJ. Clinical review: Ectopic pregnancy [published correction appears in BMJ 2000;321:424]. BMJ 2000;320:916-9.

(4.) Ankum WM, Mol BW, Van der Veen F, Bossuyt PM. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996;65:1093-9.

(5.) Mol BW, Ankum WM, Bossuyt PM, Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception 1995;52:337-41.

(6.) Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet Gynecol 1991;78:291-8.

(7.) Buckley RG, King KJ, Disney JD, Gorman JD, Klausen JH. History and physical examination to estimate the risk of ectopic pregnancy: validation of a clinical prediction model. Ann Emerg Med 1999;34:589-94.

(8.) Gallagher EJ. Application of likelihood ratios to clinical decision rules: defining the limits of clinical expertise. Ann Emerg Med 1999;34:664-7.

(9.) Mol BW, Van der Veen F, Bossuyt PM. Implementation of probabilistic decision rules improves the predictive values of algorithms in the diagnostic management of ectopic pregnancy. Hum Reprod 1999;14:2855-62.

(10.) Gracia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 2001;97:464-70.

(11.) Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med 1999;33:283-90.

(12.) Yip SK, Sahota D, Cheung LP, Lam P, Haines CJ, Chung TK. Accuracy of clinical diagnostic methods of threatened abortion. Gynecol Obstet Invest 2003:56:38-42.

(13.) Mol BW, Hajenius PJ, Engelsbel S, Ankum WM, Van der Veen F, Hemrika DJ, et al. Should patients who are suspected of having an ectopic pregnancy undergo physical examination? Fertil Steril 1999;71:155-7.

(14.) American College of Obstetricians and Gynecologists. Medical management of tubal pregnancy. Number 3, December 1998. Clinical management guidelines for obstetricians-gynecologists. Int J Gynaecol Obstet 1999;65:97-103.

(15.) American College of Emergency Physicians. Clinical policy: critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. Ann Emerg Med 2003;41:123-33.

(16.) Mol BW, Lijmer JG, Ankum WM, Van der Veen F, Bossuyt PM. The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod 1998;13:3220-7.

(17.) Barnhart K, Mennuti MT, Benjamin I, Jacobson S, Goodman D, Coutifaris C. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol 1994;84:1010-5.

(18.) Durston WE, Carl ML, Guerra W, Eaton A, Ackerson LM. Ultrasound availability in the evaluation of ectopic pregnancy in the ED: comparison of quality and cost-effectiveness with different approaches. Am J Emerg Med 2000;18:408-17.

(19.) Borrelli PT, Butler SA, Docherty SM, Staite EM, Borrelli AL, Iles RK. Human chorionic gonadotropin isoforms in the diagnosis of ectopic pregnancy. Clin Chem 2003;49:2045-9.

(20.) Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol 2004;104:50-5.

(21.) Buckley RG, King KJ, Disney JD, Ambroz PK, Gorman JD, Klausen JH. Derivation of a clinical prediction model for the emergency department diagnosis of ectopic pregnancy. Acad Emerg Med 1998;5:951-60.

(22.) Trio D, Strobelt N, Picciolo C, Lapinski RH, Ghidini A. Prognostic factors for successful expectant management of ectopic pregnancy. Fertil Steril 1995;63: 469-72.

(23.) Shalev E, Peleg D, Tsabari A, Romano S, Bustan M. Spontaneous resolution of ectopic tubal pregnancy: natural history. Fertil Steril 1995;63:15-9.

(24.) Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol 2003;101:778-84.

(25.) Hajenius PJ, Mol BW, Bossuyt PM, Ankum WM, Van der Veen F. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2000;(1):CD00324.

(26.) Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974-8.

(27.) Barnhart K, Esposito M, Coutifaris C. An update on the medical treatment of ectopic pregnancy. Obstet Gynecol Clin North Am 2000;27:653-67,viii.

(28.) Nieuwkerk PT, Hajenius PJ, Van der Veen F, Ankum WM, Wijker W, Bossuyt PM. Systemic methotrexate therapy versus laparoscopic salpingostomy in tubal pregnancy. Part II. Patient preferences for systemic methotrexate. Fertil Steril 1998;70:518-22.

ANNE-MARIE LOZEAU, M.D., M.S., and BETH POTTER, M.D.

University of Wisconsin Medical School-Madison, Madison, Wisconsin

ANNE-MARIE LOZEAU, M.D., M.S., is assistant professor of family medicine in the Department of Family Medicine at the University of Wisconsin Medical School-Madison. She received her medical degree at Dartmouth Medical School, Hanover, N.H., and completed a residency in family medicine at the University of Wisconsin Medical School-Madison.

BETH POTTER, M.D., is assistant professor of family medicine in the Department of Family Medicine at the University of Wisconsin Medical School-Madison. She received her medical degree from Rush Medical College, Chicago, and completed a residency in family medicine at the University of Wisconsin Medical School-Madison.

Address correspondence to Anne-Marie Lozeau, M.D., M.S., 3209 Dryden Dr., Madison, WI 53704 (e-mail: alozeau@wisc.edu). Reprints are not available from the authors.

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