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Ectopic pregnancy: zero in on these lab and imaging clues quantitative [beta]-hCG measurements and transvaginal ultrasound findings interpreted in light of a [beta]-hCG "cutoff" can reliably guide clinical decisions.

CASE 1 * Helen, who is 31 years old and GIP0, comes in to the office with a 10-day history of intermittent vaginal spotting without pelvic pain. A home pregnancy test 2 weeks earlier was positive, and this is a desired pregnancy. She has had no gynecologic disorders. It has been 6 weeks since her last menstrual period. Her vital signs are normal and her abdominal and pelvic exams are unremarkable. The cervical os is closed and there is a small amount of blood in the vaginal vault. Her family physician (FP) draws blood to measure the level of beta-human chorionic gonadotropin ([beta]-hCG) and orders a transvaginal ultrasound (TVUS).

CASE 2 * Mary is 28 years old and G2P1. She has experienced intermittent vaginal spotting and moderate pelvic discomfort for 3 days. She fears a return of pelvic inflammatory disease (PID). Her period is one week late and the office pregnancy test is positive. Her vital signs are normal. She has no cervical motion tenderness, but there is mild right adnexal tenderness to palpation. Her FP draws blood for a serum [beta]-hCG level and orders a TVUS.

Assess physical and history findings for perspective

Abdominal or pelvic pain and vaginal bleeding in the first trimester are the most common presenting symptoms of ectopic pregnancies. (1) Physical examination will often elicit lateral or bilateral abdominal or pelvic tenderness, peritoneal signs, and cervical motion tenderness. But such findings (or their absence) cannot confirm (or exclude) the diagnosis with a high level of reliability. (2) A woman with a positive pregnancy test and pelvic pain or vaginal bleeding may instead have a normal pregnancy, spontaneous abortion (failing intrauterine pregnancy), or a disorder such as PID, acute appendicitis, tubo-ovarian abscess, or ovarian torsion.

In an early ectopic pregnancy, vital signs are usually normal. Even in cases of ruptured ectopic pregnancy, hypotension or tachycardie is present in <40% of cases. (3)

* Factors conferring a relative risk ratio >2 for ectopic pregnancy are a previous ectopic pregnancy; documented tubal pathology or tubal instrumentation (eg, tubal sterilization or tubal corrective surgery); assisted reproductive technology such as in vitro fertilization; history of infertility; smoking; or a history of PID. (4-11)

Proceed with a laboratory and imaging strategy

When a woman who has tested positive for pregnancy presents with abdominal pain or vaginal bleeding and a normal intrauterine pregnancy (IUP) has not been confirmed by abdominal ultrasound, request a quantitative measurement of the [[beta]-hCG level and arrange for urgent TVUS. (2,13) If pregnancy has been unsuspected in a patient with these symptoms, perform a urine test for pregnancy immediately and follow up with ultrasound. (14)

If TVUS reveals either IUP or ectopic pregnancy, management is relatively straightforward. However, an inconclusive TVUS result indicates a "pregnancy of unknown location" (PUL) and necessitates further testing and follow-up to achieve a final diagnosis) (15)

Monitor [beta]-hCG levels

Valuable diagnostic measures include documenting the initial serum level of [beta]-hCG, monitoring the subsequent rise-or-fall pattern in the level, and making use of the "discriminatory cutoff" value.

[beta]-hCG, made by placental cells, can be detected in the mother's blood approximately 11 days after conception, and in the urine 12 to 14 days after conception. The serum [beta]-hCG level normally doubles every 48 to 72 hours until it reaches its peak in the first 8 to 11 weeks of pregnancy. The level then declines and plateaus.

* "Discriminatory cutoff" is a widely accepted concept signifying the level of [beta]-hCG at which a normal IUP can be visualized by ultrasonography with sensitivity approaching 100% (16) Generally an intrauterine sac can by visualized by abdominal ultrasound when the serum [beta]-hCG level is >6500 mlU/mL. (17) Visualization with TVUS (the preferred modality) has been demonstrated when the serum [beta]-hCG level is as low as 1000 mlU/mL. (17) However, the generally accepted cutoff range is 1500 to 2500 mIU/mL, based on several studies. (13,18-20) The absence of an IUP in a pregnant woman with pain or bleeding and a [beta]hCG level above the cutoff implies an ectopic pregnancy (18) or a failing IUP (spontaneous abortion).

* Serial [beta]-hCG levels. When the [beta]-hCG level is below the discriminatory cutoff, serial [beta]-hCG measurements every 2 to 3 days are needed to assess viability of the pregnancy. A "normal rise" of [beta]-hCG indicates early viable pregnancy and "normal fall" indicates spontaneous abortion. An analysis of 287 women with abdominal pain or vaginal bleeding who ultimately had normal uterine pregnancies found that the median slope for rise of [beta]-hCG was 1.5 times (50% increase) in 1 day, and 2.24 times (124% rise) in 2 days. (21) A rapid fall in [beta]-hCG is consistent with a miscarriage that may resolve spontaneously. However, if the [beta]-hCG level does not decline by 21% to 35% in 2 days, suspect ectopic pregnancy. (21)

Arrange for transvaginal ultrasound

TVUS is the imaging modality of choice for diagnosis of ectopic pregnancy, with a sensitivity of 87.0% to 99.0% and specificity of 94.0% to 99.9%. (22) Arrange for TVUS when a women has abdominal pain or vaginal bleeding and a positive urine pregnancy test, even if the [beta]-hCG level is lower than the discriminatory cutoff of 1500 to 2500 mIU/mL. (13,18-20) Ordering TVUS and [beta]-hCG level at the same time yields the best outcome for diagnosis, (19) while varying the discriminatory zone alone has not improved diagnosis. (18,23)

Other novel markers

The use of serum progesterone and other novel markers such as inhibin A, activin A, creatinine kinase, vascular endothelial growth factor, and cancer antigen 125 in the diagnosis of ectopic pregnancy has been studied extensively. To date, no single marker has demonstrated high sensitivity and specificity in differentiating ectopic pregnancy. (24) However, when the initial progesterone level is [less than or equal to]10 nmol/L (equivalent to 31.4 ng/mL) in a woman with a PUL, the probability that she will require any intervention is reported to be low (4 cases out of 227 PUL cases). (25) Multiplex tools to combine multiple biomarkers may become available in the future.

Evacuation of uterine contents

When the [beta]-hCG level is above the discriminatory cutoff but no evidence of an extrauterine or intrauterine pregnancy can be found by TVUS, the patient likely has a failing IUP or impending abortion. Some experts suggest considering evaluation of the uterine contents by dilation and curettage (D&C) or manual vacuum extraction at this time, to differentiate an abnormal intrauterine gestation from an ectopic pregnancy. Barnhart found that more than one-third of such cases were due to a failed uterine pregnancy, not ectopic pregnancy. (26)

If, after a D&C or manual extraction, chorionic villi are not confirmed by pathologic examination of the uterine contents, then treat as an ectopic pregnancy. Some clinicians alternatively recommend checking the [beta]-hCG level again in 12 to 24 hours, expecting [greater than or equal to] 15% decline with a spontaneous abortion. (27) Alternatively, some recommend using methotrexate (MTX) without D&C to avoid unnecessary medical and surgical treatment, (26)

CASE 1 *

Helen's serum [beta]-hCG level is 4500 mlU/mL, and the TVUS image the next day shows an echogenic mass next to the right ovary--highly suspicious for ectopic pregnancy.

CASE 2 *

Mary's TVUS does not show any evidence of IUP or any abnormality in either adnexa. Her serum [beta]-hCG level is 650 mlU/mL. She has a PUL. Her FP informs her that she may have an early normal pregnancy, a failed IUP, or an ectopic pregnancy. She agrees to have her serum [beta]-hCG measured every 2 days. Her [beta]-hCG level increases to 1100, 2000, and 3500 mlU/mL, in 2, 4, and 6 days, respectively. TVUS on the sixth day is still nondiagnostic.

Treatment of ectopic pregnancy: Surgical vs medical

For hemodynamically unstable patients, laparotomy is still the mainstay of therapy. However, with early diagnosis and a stable patient, options are minimally invasive surgical intervention via laparostomy or medical management with MTX in a single or multidose regimen. Surgical and medical treatments have comparable outcomes, as documented by a Cochrane review. (28)

The risk of recurrent ectopic pregnancy after MTX treatment and salpingostomy is similar--about 10%. (29) Ipsilateral tubal patency as documented by hysterosalpingography after MTX treatment or salpingostomy was reported to be equal. (28) Reproductive outcomes after either treatment were similar, as well. (30)

* We recommend urgent referral for OB/GYN consultation if the diagnosis of ectopic pregnancy is made by TVUS, since the recommended treatment is laparoscopic salpingostomy. In the case of a PUL, we recommend referral to an OB/GYN when the serum [beta]-hCG level is above the discriminatory cutoff of 1500 to 2500 mIU/mL without signs of IUP as seen by a gestational sac via TVUS. When an urgent referral is not possible, initiate medical treatment. Regardless of the treatment method, give anti-D immunoglobulin to any woman whose blood is Rh negative (no D-antigen) and who has not been sensitized to D-antigen.

Surgical management

Laparoscopic salpingostomy is the preferred surgical treatment for ectopic pregnancy. A Cochrane review meta-analysis of 35 randomized controlled trials (RCTs) on intervention of ectopic pregnancy concluded that, compared with laparotomy, laparoscopy results in shorter operative time, less blood loss, less analgesia, shorter hospital stays, and greater cost effectiveness. (28) Another meta-analysis of 15 RCTs concluded that laparoscopic salpingostomy is the most cost-effective treatment for ectopic pregnancy. (31)

Medical management with methotrexate

This folic acid antagonist is highly effective in treating ectopic pregnancy, and is usually given intramuscularly for this indication. Clinicians who use this chemotherapeutic agent must be familiar with its dosing regimen, contraindications, and possible adverse effects. Multidose MTX is more effective than surgery, but more expensive. (32) Single-dose MTX has a higher failure rate than laparoscopic salpingostomy, especially in patients with higher [beta]-hCG levels? (32)

* The best candidate for medical therapy is the woman who is asymptomatic, motivated, and compliant. Absolute contraindications to single-dose MTX include the following:

** breastfeeding

** overt or lab evidence of immunodeficiency

** alcoholism, alcoholic liver disease, or other chronic liver disease

** preexisting blood dyscrasias, such as bone marrow hypoplasia, leucopenia, thrombocytopenia, or significant anemia

** known sensitivity for methotrexate

** acute pulmonary disease

** peptic ulcer disease

** hepatic, renal, or hematologic dysfunction, and several metabolic diseases. (33)

* Dosing regimen, The 3 general dosing schemes of single dose, 2-dose, and multidose (up to 4 doses) are shown in the TABLE. These were recommended by the American College of Obstetrician and Gynecologists (ACOG). (33)

* Single dose vs multidose, The single-dose treatment is easier to administer and monitor and is most cost effective, but it may have a higher failure rate than the multidose regimens. (28) The best prognostic indicator of successful treatment with single-dose MTX is the initial [beta]-hCG level. The lower the initial level, the higher the success rate. The reported failure rate is 1.5% if the initial [beta]-hCG level is <1000 mIU/mL; 5.6% with 1000 to 2000 mIU/mL; 3.8% with 2000 to 5000 mlU/mL; and 14.3% with 5000 to 10,000 mlU/mL. (34) ACOG has outlined relative contraindications to single-dose MTX: ectopic pregnancy larger than 3.5 cm and the presence of fetal cardiac activity. Both cor relate with an increased failure rate. Patients with PUL and low [beta]-hCG levels are good candidates for single-dose MTX treatment.

Monitoring efficacy of treatment

Serum [beta]-hCG levels indicate response to medical and surgical therapy. After salpingostomy, the serum [beta]-hCG level declines rapidly within the first 4 days, and then more gradually, with mean resolution occurring at about 20 days. In contrast, after single-dose MTX, the mean serum [beta]-hCG level increases for the first 4 days and then gradually declines, with a mean resolution at 27 days. (35) q-he guideline for surveillance is shown in the TABLE.

CASE 1 *

The FP counsels Helen on the risks and benefits of surgery and MTX treatment for her ectopic pregnancy, and she elects to have a laparoscopic salpingostomy. The FP refers Helen to an OB/GYN via the emergency department on the same day. Helen does well. After the surgery, her [beta]-hCG is monitored every 2 days until it decreases to 1000 mlU/mL, then every week until it is negative.

CASE 2 *

The FP advises Mary that an OB/GYN would likely recommend a D&C for her PUL, as her [beta]-hCG level is above the discriminatory cutoff and the "I'VUS does not show a viable IUR After discussing MTX treatment and manual vacuum aspiration of the uterine contents, Mary elects to have the MTX treatment and receives the 2-dose protocol. Her [beta]-hCG level is 4210 mlU/mL on Day 1--higher than her level prior to the methotrexate treatment, but expected. Levels drop to 3635, 3102, and 2214 mlU/mL on Days 4, 7, and 10, respectively. Mary receives weekly surveillance until her level decreases to 0, which it did in a month. 3FP

PRACTICE RECOMMENDATIONS

* Administer a urine pregnancy test for women of childbearing age who present with abdominal pain or vaginal bleeding. (C)

* Initiate quantitative beta-human chorionic gonadotropin testing and order transvaginal ultrasound for women with abdominal pain or vaginal bleeding and a positive urine pregnancy test, but no confirmation of intrauterine pregnancy by abdominal ultrasound. (B)

* Refer hemodynamically stable patients with ectopic pregnancy for laparoscopic salpingostomy. For selected patients, an alternative is medical treatment with methotrexate. (A)

Strength of recommendation (SOR)

(A) Good-quality patient-oriented evidence

(B) Inconsistent or limited-quality patient-oriented evidence

(C) Consensus, usual practice, opinion, disease-oriented evidence, case series

The authors reported no potential conflict of interest relevant to this article.

References

(1.) Aboud E, Chafiha C. Nine year survey of 138 ectopic pregnancies. Arch Gynecol Obstet. 1998;261:83-87.

(2.) Dart GD, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med. 1999;33:283-290.

(3.) Birkhahn RH, Gaeta TI, Van Deusen SK, et al. The ability of traditional vital signs and shock index to identify ruptured ectopic pregnancy. Am J Obstet Gynecol. 2003;189:1293-1296.

(4.) Cunningham FG, Leveno KJ, Bloom SL, et al. Ectopic pregnancy. In: Cunningham FG, Leveno KJ, Bloom SL, et al, eds. Williams Obstetrics. 23rd ed. New York, NY: McGraw-Hill; 2010:238-256.

(5.) Bakken IJ, Skjeldestad FE, Lydersen S, et al. Births and ectopic pregnancies in a large cohort of women tested for Chlamydia trachomatis. Sex Transm Dis. 2007;34:739-743.

(6.) Bakken IJ, Skjeldestad FE, Nordbo SA. Chlamydia trachomatis infections increase the risk for ectopic pregnancy: a population-based, nested case-control study. Sex Transm Dis. 2007;34: 166-169.

(7.) Barnhart KT, Sammel MD, Gracia CR, et al. Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies. Fertil Steril. 2006;86:36-43.

(8.) Bouyer I, Coste J, Shojaei T, et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France. Am J Epidemiol. 2003;157: 185-194.

(9.) Gala RB. Ectopic pregnancy. In: Schorge JO, Schaffer JI, Halvorson LM, et al, eds. Williams Gynecology. New York, NY: McGraw-Hill; 2008:160-175.

(10.) Karaer A, Avsar FA, Batioglu S. Risk factors for ectopic pregnancy: a case-control study. Aust N Z J Obstet Gynaecol. 2006;46: 521-527.

(11.) Virk J, Zhang I, Olsen 1. Medical abortion and the risk of subsequent adverse pregnancy outcomes. N Engl J Med. 2007;357: 648-653.

(12.) Dart RG, Kaplan B, Cox C. Transvaginal ultrasound in patients with low beta-human chorionic gonadotropin values: how often is the study diagnostic? Ann Emerg Med. 1997;30:135-140.

(13.) Kaplan BC, Dart RG, Moskos M, et al. Ectopic pregnancy: pm spective study with improved diagnostic accuracy. Ann Emerg Med. 1996;28:10-17.

(14.) Clinical policy: critical issues for the initial evaluation and management of patients presenting with a chief complaint of nontraumatic acute abdominal pain. Ann Emerg Meal. 2000;36: 406-415.

(15.) Barnhart K, van Mello NM, Bourne T, et al. Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome. Fertil Steril. 2011;95:857-866.

(16.) Barnhart K, Mennuti MT, Benjamin I, et al. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol. 1994;84:1010-1015.

(17.) Aleem FA, DeFazio M, Gintautas I. Endovaginal sonography for the early diagnosis of intrauterine and ectopic pregnancies. Hum Reprod. 1990;5:755-758.

(18.) Coundous G, Kirk E, Lu C, et al. Diagnostic accuracy of varying discriminatory zones for the prediction of ectopic pregnancy in women with a pregnancy of unknown location. Ultrasound Obstet Gynecol. 2005;26:770-775.

(19.) Gracia CR, Kurt TB. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol. 2001;97: 464-470.

(20.) Kohn MA, Kerr K, Malkevich D, et al. Beta-human chorionic gonadotropin levels and the likelihood of ectopic pregnancy in emergency department patients with abdominal pain or vaginal bleeding. Acad Emerg Med. 2003; 10: l19-126.

(21.) Barnhart K, Sammel MD, Chung K, et al. Decline of serum human chorionic gonadotropin and spontaneous complete abortion: defining the normal curve. Obstet Gynecol. 2004;104: 975-981.

(22.) Kirk E, Bourne 11 Diagnosis of ectopic pregnancy with ultrasound. Best Pract Res Clin Obstet Gynaecol. 2009;23:501-508.

(23.) van Mello NM, Mol E Opmeer BC, et al. Diagnostic value of serum hCG on the outcome of pregnancy of unknown location: a systematic review and recta-analysis. Hum Reprod Update. 2012;18:603-617.

(24.) Segal S, Mercado R, Rivnay B. Ectopic pregnancy early diagnosis markers. Minerva Ginecol. 2010;62:49-62.

(25.) Cordina M, Schramm-Gajraj K, Ross JA, et al. Introduction of a single visit protocol in the management of selected patients with pregnancy of unknown location: a prospective study. BIOG. 2011;118:693-697.

(26.) Bamhart KT, Katz I, Hummel A. Presumed diagnosis of ectopic pregnancy. Obstet Gynecol. 2002; 100:505-510.

(27.) Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol. 2006;107:399-413.

(28.) Hajenius PJ, Mol E Mol BW, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev. 2007;(1):CD000324.

(29.) Stovall TG. Medical management should be routinely used as primary therapy for ectopic pregnancy. Clin Obstet Gynecol. 1995;38:346-382.

(30.) Fernandez H, Yves Vincent SC, Pauthier S, et al. Randomized trial of conservative laparoseopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility. Hum Reprod. 1998;13:3239-3243.

(31.) Mol F. Strandell A, Jurkovic D, et al. The ESEP study: salpingosto my versus salpingectomy for tubal ectopic pregnancy; the impact on future fertility: a randomised controlled trial. BMC Womens Health. 2008;8:11.

(32.) Mol E Mol BW, Ankum WM, et al. 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. 2008;14:309-319.

(33.) American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 94. Medical management of ectopic pregnancy. Obstet Gynecol. 2008;111:1479-1485.

(34.) Menon S, Colins J, Barnhart KT. Establishing a human chorionic gunadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril. 2007;87: 481-484.

(35.) Saraj AJ, Wilcox JG, Najmabadi S, et al. Resolution of hormonal markers of ectopic gestation: a randomized trial comparing single-dose intramuscular methotrexate with salpingostomy. Obstet Gynecol. 1998;92:989-994.

Sahoko H. Little, MD; Pamela G. Rockwell, DO Department of Family Medicine, University of Michigan, Ann Arbor

sahoko@med.umich.edu

CORRESPONDENCE

Sahoko H. Little, MD, Room 2300, Lobby H, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48105-9755; sahoko@med. umich.edu
TABLE
Monitoring methotrexate therapy for ectopic pregnancy

Obtain a complete blood count with differential and liver and renal
function tests before starting any regimen.

Regimen                            Surveillance

Single dose*                       Measure [beta]-hCG level on Days 4
                                   and 7:

Methotrexate, 50 mg/[m.sup.2] IM     If difference [greater than or
                                       equal to] 15%, repeat weekly
                                       until undetectable
                                     If difference <15%, repeat
                                       methotrexate dose and begin
                                       new Day 1

                                   If fetal cardiac activity present
                                   on Day 7, repeat methotrexate dose
                                   and begin new Day 1

                                   Refer for surgical treatment if
                                   [beta]-hCG level is not decreasing
                                   or fetal cardiac activity persists
                                   after 3 methotrexate doses

2 dose                             Follow up as for single-dose
                                   regimen
Methotrexate, 50 mg/m.sup.2] IM,
Days 0, 4

Multidose (up to 4 doses)          Measure [beta]-hCG level on Days
                                   1, 3, 5, and 7

Methotrexate, 1 mg/kg IM, Days       Continue alternate-day
1, 3, 5, 7                           injections until [beta]-hCG
Leucovorin, 0.1 mg/kg IM, Days       level decreases [greater than
2, 4, 6, 8                           or equal to] 15% in 48 hours or
                                     4 doses of methotrexate have
                                     been given. Then, weekly
                                     [beta]-hCG measurement until
                                     undetectable

[beta]-hCG, beta-human chorionic gonadotropin; IM, intramuscularly.

* Preferred treatment if low initial [beta]-hCG level.

Adapted from: Seeber BE, et al. Obstet Gynecol. 2006. (27)
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Author:Little, Sahoko H.; Rockwell, Pamela G.
Publication:Journal of Family Practice
Article Type:Case study
Date:Nov 1, 2012
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