Ectopic Pregnancy

Ectopic Pregnancy Update
Author: Jennifer Robertson, MD (EM Attending Physician, Cleveland Clinic) // Editor: Alex Koyfman, MD

General Info/Intro
Ectopic pregnancy is a common and potentially fatal emergency in early pregnancy (1,2). Its prevalence is about 2% in the general population (2), but is as high as 16% in women presenting to the emergency department with concerning symptoms (1,3). Ectopic pregnancy is a cause of pregnancy-related death and can also lead to chronic pelvic pain, need for blood transfusions, and long-term infertility (2,4). Because of the potentially devastating outcomes, it is imperative that emergency physicians diagnose ectopic pregnancy early and refer patients to the proper specialist care.

Recap Basics
Ectopic pregnancy is usually diagnosed in the first trimester of pregnancy, most commonly at six to ten weeks gestational age (1). Risk factors include prior ectopic, history of a tubal ligation or prior tubal surgery, pelvic inflammatory disease (PID), and infertility (5,6). Symptoms and exam findings really depend on whether tubal rupture has occurred. Signs and symptoms can vary from just pelvic pain or vaginal bleeding to bleeding from massive intraperitoneal hemorrhage (1,7). While most women do present with abdominal pain and vaginal bleeding, up to 9% of women have no pain at all (7). In addition, more than half of all ectopic pregnancies occur in women without any known risk factors (8). Thus, ectopic pregnancy can be a difficult diagnosis to make and physicians should maintain high clinical suspicion, even in patients with minimal symptoms and benign exam findings.

The diagnosis of ectopic pregnancy is typically made by confirmation of pregnancy with a positive urine beta human chorionic gonadotropin (Β-hCG) and a pelvic ultrasound showing an extra-uterine pregnancy (9). If the ultrasound shows an intrauterine pregnancy (IUP), then ectopic can typically be ruled out since the incidence of concomitant ectopic and IUP is extremely low (3).

The difficulty in diagnosing ectopic pregnancy lies in the inconclusive ultrasound results. If the ultrasound is inconclusive, then a serum Β-hCG level is drawn to see if it is greater or less than the “discriminatory zone”. By definition, the discriminatory zone is the minimum serum β-hCG concentration at which ultrasound is 100% sensitive in identifying an IUP (10,11). Currently, most hospitals have a discriminatory zone of 1000 to 2000 IU/I (3,12). The diagnosis of ectopic pregnancy is then made if an IUP is not visualized when the β-hCG is above the defined discriminatory zone. If the serum β-hCG is less than the discriminatory zone, then the pregnancy may be an ectopic, a spontaneous abortion, or simply an early IUP (9). Patients are typically sent home with instructions to repeat β-hCG levels and obtain close follow-up.

The problem with the above plan, however, is that ectopic pregnancies can present at almost any β-hCG level (3). In addition, in patients with indeterminate ultrasounds, the serum β-hCG is not predictive of ectopic pregnancy at all (13,14). Literature has shown moderately high sensitivities of ultrasound in diagnosing ectopic pregnancy in patients with β-hCG of under 1000 IU/I (15,16,17) . Below, in the “What’s New” section, the current American College of Emergency Physicians (ACEP) policy regarding the difficulties in diagnosing ectopic pregnancy will be addressed as well as potential future biomarkers to help reduce some of these difficulties.

Treatment will vary depending on hemodynamic stability, pre-treatment β-hCG concentration, and the ability of patients to comply with follow-up (1). If unstable, patients should be resuscitated as any unstable patient. A type and screen should always be obtained and Rhogam® administered to Rh-negative patients as per ACEP Clinical Policy (10,18). Thereafter, for all other stable patients, expectant, medical or surgical management may be options. All options should be discussed with the consulting obstetric specialist.

Ectopic pregnancy can resolve spontaneously, but many women require treatment with methotrexate or surgery. Expectant management should be offered only when serum levels of β- hCG and progesterone are low and declining and ultrasound does not show the location of the gestational sac (1). Patients must then be monitored closely until the serum β-hCG levels fall below 15 IU/L (1).

All other patients will require surgery or medical therapy with methotrexate. Criteria for methotrexate include absence of ultrasound evidence of fetal cardiac activity, hemodynamic stability, pre-treatment β-hCG concentration less than 5,000 IU/L , and the ability of patients to comply with follow-up (1). It is contraindicated in patients with alcoholism, immunodeficiency, peptic ulcers, or active disease of the lungs, liver, kidneys, or hematopoietic system (18). It is also relatively contraindicated in patients with a gestational sac larger than 3.5 cm or with cardiac motion observed on ultrasound (18).

The 2012 ACEP Clinical Policy also addresses treatment with methotrexate, namely, the ED management of patients taking the medication (10). One can refer to the policy, but essentially the authors recommend close follow-up as well as keeping a strong suspicion of rupture in patients who have received methotrexate and have concerning symptoms. Finally, surgery is typically conducted in patients who refuse or have contraindications to medical treatment, those in whom medical treatment has failed, and those who are hemodynamically unstable (1).

What’s New
In 2012, the American College of Emergency Physicians (ACEP) addressed issues mentioned above in an update of their clinical policy on the evaluation and management of patients in early pregnancy (10). Overall, based on panel consensus or class III studies, the authors recommend obtaining a pelvic ultrasound for symptomatic pregnant patients with a β-hCG level below any discriminatory level. The authors do say that at this time, there is not enough evidence to estimate risk of rupture or death if an ultrasound is not obtained, but essentially this may reduce delays in diagnosis (10).

In regards to the use of serum β-hCG levels in determining risk of ectopic pregnancy, ACEP indicates that, based on class II studies or strong class III studies, that the β-hCG value should not be used to exclude the diagnosis of ectopic pregnancy in patients who have an indeterminate ultrasound. They also recommend that, based on panel consensus or class III studies, consultation and/or close follow-up should be arranged for patients with an indeterminate US. The article is listed below for further review (10).

Finally, no matter the type of treatments stated above, it is important to initiate treatment early to avoid potential morbidity and mortality of ectopic pregnancy. However as previously mentioned, the diagnosis of ectopic pregnancy is not easy and can often lead to a delay in these treatments. (4). Thus, there is a strong need for other tools in diagnosing ectopic pregnancy (4,11). Currently, research is evaluating over 20 possible biomarkers that could be used to diagnose ectopic pregnancy. These biomarkers are divided into separate areas including markers of abnormal embryo/trophoblast growth (hCG; AFP, Activin A), markers of abnormal corpus luteum function (progesterone, inhibin A, relaxin), markers of a growing pregnancy in the Fallopian tube (CK, myoglobin, VEGF), markers of inflammation and peritoneal irritation (CA 125, TNF, IL-2/6/8), and uterine markers of normal implantation (e.g. Activin B) (4,11,19). Unfortunately, the clinical utility of biomarkers has been limited because of limitations in study designs (20). However, biomarkers may be the wave of the future in the diagnosis of ectopic pregnancy and emergency physicians should be on the lookout for their potential use.

Bottom Line/Pearls & Pitfalls
– Ectopic pregnancy is a difficult diagnosis to make
– It can present in any woman of childbearing age with pelvic pain, vaginal bleeding or even no pain at all
– Ectopic pregnancy can be possible, even with very low serum quantitative β-hCG levels
– Clinicians should obtain an ultrasound, even with very low serum quantitative β-hCG levels
– Treatment will vary depending on the patient, makes sure to always consult an OB-GYN
– If sending a patient home, make sure they have adequate and close follow-up
– Biomarkers may be the wave of the future

Further Reading
– Hahn SA, Lavonas EJ, Mace SE, et al. Clinical policy: Critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. Ann Emerg Med 2012; 60:381-390.
– http://www.ncbi.nlm.nih.gov/pubmed/24342865

Discussion Questions
Is it cost effective and efficient enough to obtain an ultrasound on every pregnancy woman with a suspected ectopic and a serum β-hCG level less than the “discriminatory range”?

References
1. Murray H, Baakdah H, Bardell T, Tulandi T. Diagnosis and treatment of ectopic pregnancy. CMAJ 2005; 173:905.
2. Centers for Disease Control and Prevention (CDC). Ectopic pregnancy–United States, 1990-1992. MMWR Morb Mortal Wkly Rep 1995; 44:46.
3. 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.
4. Horne AW, Duncan WC, Critchley HO. The need for serum biomarker development for diagnosing and excluding tubal ectopic pregnancy. Acta Obstet Gynecol Scand 2010; 89(3): 299–301.
5. Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril 1996; 65 (6): 1093-1099.
6. Kamwendo F, Forslin L, Bodin L, Danielsson D. Epidemiology of ectopic pregnancy during a 28 year period and the role of pelvic inflammatory disease. Sex Transm Infect 2000; 76:28.
7. Tay JI, Moore J, Walker. Ectopic pregnancy. BMJ 2000; 320(7239): 916–919.
8. Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med 1999; 33 (3): 283-90.
9. Gracia C, Barnhart K. Diagnosing ectopic pregnancy: Decision analysis comparing six strategies. Obstet Gynecol 2001; 97 (3): 464-70.
10. Hahn SA, Lavonas EJ, Mace SE, et al. Clinical policy: Critical issues in the initial evaluation and management of patients presenting to the emergency department in early pregnancy. Ann Emerg Med 2012; 60:381-390.
11. Cartwright J, Duncan WC, Critchley HD, et al. Serum biomarkers of tubal ectopic pregnancy: current candidate and future possibilities. Reproduction 2009; 138: 9–22.
12. Barnhart KT, Simhan H, Kamelle S. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol 1999; 94 (4): 583-87.
13. Condous G, Kirk E, Van Huffel S, 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.
14. Condous G, Okaro E, Khalid A, et al. A prospective evaluation of a single visit strategy to manage pregnancies of unknown location. Hum Reprod 2005; 20 (5): 1398-1403.
15. Counselman FL, Shaar GS, Heller RA, et al. Quantitative β-hCG levels less than 1000 mIU/mL in patients with ectopic pregnancy: pelvic ultrasound still useful. J Emerg Med 1998; 16 (5): 699-703.
16. Adhikari S, Blaivas M, Lyon M. Diagnosis and management of ectopic pregnancy using bedside transvaginal ultrasonography in the ED: a 2-year experience. Am J Emerg Med 2007; 25 (6): 591-596.
17. Cacciatore B. Can the status of tubal pregnancy be predicted with transvaginal sonography? A prospective comparison of sonographic, surgical and serum hCG findings. Radiology 1990; 177 (2): 481-484.
18. 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;41:123-133.
19. American College of Obstetricians and Gynecologists. Practice bulletin No 94: Medical management of ectopic pregnancy. Obstet Gynecol 2008; 111 (6): 1479-85.
20. Senapati S, Barnhart KT. Biomarkers for ectopic pregnancy and pregnancy of unknown location. Fertil Steril 2013; 99 (4): 1107-1116.
21. Wedderburn CJ, Warner P, Graham B, et al. Economic evaluation of diagnosing and excluding ectopic pregnancy. Hum Reprod 2010; 25 (2): 328-333

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Jennifer Robertson