For female patients presenting to the emergency department with a positive serum β-HCG as well as abdominal pain, vaginal bleeding, syncope, or hypotension, the prudent emergency physician must rule out an ectopic pregnancy (EP). This potentially life-threatening entity is estimated to occur in 1.5 to 2% of all pregnancies and ruptured ectopic pregnancies account for 6% of all maternal deaths [cite num=”1″]. Point-of-care ultrasound (either trans-abdominal or trans-vaginal) has become the standard of care when assessing a patient for possible EP as the finding of an intrauterine pregnancy (IUP) can rule out an EP, assuming no risk factors for heterotopic pregnancy (fertility treatment is by faaaar the biggest one that needs to be considered) [cite num=”2″].
However, in approximately 20-30% of cases, the ultrasound will fail to reveal an IUP which leaves the emergency physician no further ahead [cite num=”3,4,5″]. Some diagnostic algorithms propose that at this point, the physician should use the “β-HCG discriminatory zone” to assess for the likelihood of an EP [cite num=”6″]. This level is defined as the serum β-HCG level above which ultrasound is expected to detect a viable IUP. Classically, this level is defined as a β-HCG level of 1,500 mIU/mL for trans-vaginal and 6,000 mIU/mL for trans-abdominal ultrasound.
Thus, if a patient’s serum β-HCG level is above the discriminatory zone and the woman has no visible IUP on ultrasound, we are told that the physician should be very concerned for the possibility of an EP. Should the physician be any less concerned about the possibility of an EP if the β-HCG level is below the discriminatory zone? Is it just too early for an IUP to be seen on ultrasound with lower levels of β-HCG? Let’s take a look at the literature…
A 23-year-old woman presents to your Emergency Department with two days of lower pelvic pain and vaginal bleeding. She tells you she missed her last menstrual period so she took a home pregnancy test which was positive. Her last menstrual period was about eight weeks ago. This is her first pregnancy and she is otherwise healthy with no medical issues or routine medications. Upon further questioning you find out she has been treated for Chlamydia several times.
Your examination reveals a woman who is slightly diaphoretic and very anxious. Her vitals are stable. Her abdomen is soft but tender to the lower abdomen, particularly at the left lower quadrant. There is no rebound tenderness. A speculum exam reveals scant blood in the vaginal canal but a closed cervix. A bimanual exam is unremarkable.
A bedside transvaginal ultrasound is unable to identify an IUP. You order a serum β-HCG level which comes back at 606 mIU/mL.
The Clinical Question
How useful is the β-HCG discriminatory zone in a suspected ectopic pregnancy?
The Evidence for the discriminatory zone
- In 1996, Kaplan et al. performed a study of 403 women with first-trimester abdominal pain or bleeding presenting to the emergency department. The risk of EP with an indeterminate ultrasound and a β-HCG level <1,000 mIU/mL was 10/25 (40%), while the risk of an EP with an indeterminate ultrasound and β-HCG level >1,000 mIU/mL was 5/47(11%). The overall incidence of EP in these high risk women was 13% [cite num=”3″].
- A study by Mol et al. (1998) included 354 stable pregnant women with complaints such as abdominal pain or vaginal bleeding. The LR for EP in patients without adnexal mass or free fluid was: 0.62 if β-HCG level <1,000 mIU/mL, 0.31 if β-HCG level 1,000 – 1,499 mIU/mL, 0.63 if β-HCG level 1,500 – 1,999 mIU/mL and 19 if β-HCG level >2,000 [cite num=”7″].
- Dart et al. (2002) completed a study evaluating 635 female patients with indeterminate ultrasound results presenting with abdominal pain and vaginal bleeding. The EP rate with a β-HCG level discriminatory zone <1,000 mIU/mL was 15% and >1,000 mIU/mL was 2%. The overall incidence of EP was 7% (46 of 635) [cite num=”4″].
- In 2005, Condous et al. investigated 527 stable symptomatic and asymptomatic pregnant patients with indeterminate ultrasound findings. Then sensitivity and specificity for various discriminatory thresholds were, respectively, 22% and 87% for a β-HCG level of 1,000, 15% and 93% for a β-HCG level of 1,500, and 11% and 95% for β-HCG level of 2,000. The overall incidence of EP was 9% (46 of 527) [cite num=”8″].
- Wang et al. (2011) completed a study of 256 stable first-trimester pregnant women who presented to the emergency department with abdominal pain, vaginal bleeding, or syncope. Of the 256 patients, 141 had indeterminate ultrasound results. Using a β-HCG discriminatory level of 3,000 mIU/mL achieved a sensitivity of 25%, specificity of 58%, +LR 0.82, and –LR 1.13. There was no β-HCG discriminatory zone cutoff at which 100% of the IUPs were visualized. Overall incidence of EP was 11% [cite num=”5″].
Summary of Test Characteristics
+LR = risk of an EP when the β-HCG level is above the discriminatory zone
-LR = risk of an EP when the β-HCG level is below the discriminatory zone
|β-HCG Discriminatory Zone (mIU/mL)||Study||Number of Patients||
+LR (95% CI)
– LR (95% CI)
|1,000||Kaplan 1996 [cite num=”3″]||72||0.5 (0.2 – 0.9)||2.5 (1.4 – 4.5)|
|Mol 1998 [cite num=”7″]||262||3.1 (2.0 – 4.8)||0.7 (0.5 – 0.8)|
|Dart 2002 [cite num=”4″]||635||0.3 (0.2-0.5)||2.3 (1.9 – 2.7)|
|Condous 2005 [cite num=”8″]||527||1.7 (0.9 – 3.1)||0.9 (0.8 – 1.0)|
|1,500||Condous 2005 [cite num=”8″]||527||2.3 (1.1 – 4.9)||0.9 (0.8 – 1.0)|
|2,000||Mol 1998 [cite num=”7″]||262||25 (7.9 – 81)||0.6 (0.5-0.8)|
|Condous 2005 [cite num=”8″]||527||2.3 (0.9 – 5.7)||0.9 (0.8 – 1.0)|
|3,000||Wang 2011 [cite num=”5″]||141||0.8 (0.5 – 1.4)||1.1 (0.8 – 1.5)|
This idea of the discriminatory zone – that a physician should be concerned for an EP if a woman has no visible IUP on ultrasound and a β-HCG level above the discriminatory zone – is not as well supported in the literature as we were previously led to believe. Only one study by Mol et al. (1998) was able to generate a large enough positive likelihood ratio that would support this claim and significantly alter clinical decision making [cite num=”7″]. Meanwhile, other studies such as Kaplan et al. (1996) and Wang et al. (2011) found that patients with an indeterminate ultrasound and a β-HCG level below the defined discriminatory zone were at higher risk for ectopic pregnancy [cite num=”3,5″].
In reality, a woman with an ectopic pregnancy can present at almost any β-HCG level as evidenced by the study by Barnhart et al. (1994). It revealed that patients with ruptured ectopic pregnancies could present with a β-HCG level from as low as 10 to as high as 189,270 mIU/mL [cite num=”9″]. Moreover, a recent study by Ko et al. (2014) found that even if a woman has an indeterminate ultrasound and a β-HCG level above the discriminatory zone, she is just as likely to have a viable IUP as she is to have an EP. They found the highest β-HCG level without an initially detectable IUP was 9,083 mIU/mL which then went on to develop into a viable IUP [cite num=”10″].
In 2012, the American College of Emergency Physicians provided a Level B recommendation to discard the use the β-HCG discriminatory zone to exclude the diagnosis of EP in patients who have an indeterminate ultrasound and a Level C recommendation to obtain specialty consultation and arrange close follow-up for those with indeterminate ultrasound results [cite num=”11″]. Instead, if the patient is stable then the physician should obtain a thorough history assessing for risk factors of ectopic pregnancy, obtain a formal ultrasound, and trend the β-HCG for doubling in 48 hours. More appropriate diagnostic algorithms have been developed that take these recommendations into account and do not use the discriminatory zone [cite num=”12″].
The Bottom Line
ED physicians can confidently rule out an EP when there is a visible IUP on bedside ultrasound assuming there are no risk factors for heterotopic pregnancy. However, if the ultrasound is unable to identify an IUP and the β-HCG level is above the discriminatory zone, studies have shown this may be an EP or an early IUP. In contrast, if the ultrasound is indeterminate and the β-HCG level is below the discriminatory zone, this could also represent an EP or early IUP, with some studies indicating that these patients are actually at higher risk for EP, which contradicts the classical teaching of the discriminatory zone. It has been demonstrated that EPs can occur at virtually any β-HCG level. Strict adherence to the use of the discriminatory zone to diagnose EPs can lead to an unnecessary disruption of a normal pregnancy and can also lead to missed EPs. Therefore, clinicians should no longer rely on the use of the discriminatory zone to exclude the diagnosis of EP as recommended by ACEP in 2012. Instead, appropriate follow-up with formal ultrasound examinations paired with trending of the β-HCG rise over time are far more important for all women with indeterminate ultrasound results.
- Barnhart KT Clinical practice. Ectopic pregnancy. N Engl J Med. 2009; 361(4): 379-87. PMID: 19625718
- Stein JC, Wang R, Adler N, et al. Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. Ann Emerg Med. 2010; 56(6): 674-83. PMID: 20828874
- Kaplan BC, Dart RG, Moskos M, et al. Ectopic pregnancy: prospective study with improved diagnostic accuracy. Ann Emerg Med. 1996; 28(1): 10-7. PMID: 8669724
- Dart RG, Burke G, Dart L. Subclassification of indeterminate pelvic ultrasonography: prospective evaluation of the risk of ectopic pregnancy. Ann Emerg Med. 2002; 39(4): 382-8. PMID: 11919524
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- Mol BW, Hajenius PJ, Engelsbel S, et al. Serum human chorionic gonadotropin measurement in the diagnosis of ectopic pregnancy when transvaginal sonography is inconclusive. Fertil Steril. 1998; 70(5): 972-81. PMID: 9806587
- Condous 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(7): 770-5. PMID: 16308901
- 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(6): 1010-5. PMID: 7970455
- Ko JK, Cheung VY. Time to revisit the human chorionic gonadotropin discriminatory level in the management of pregnancy of unknown location. J Ultrasound Med. 2014; 33(3): 465-71. PMID: 24567458
- Hahn SA, Lavonas EJ, Mace SE, Napoli AM, Fesmire FM, American College of Emergency Physicians Clinical Policies Subcommittee on Early Pregnancy. 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(3): 381-90.e28. PMID: 22921048
- Micks T, Sue K. The occasional ectopic pregnancy. Can J Rural Med. 2015; 20(4): 139-44. PMID: 26447733