When a patient’s pregnancy test is positive but ultrasound is inconclusive, a stepwise approach is essential to make an accurate-and timely-diagnosis.
Differentiating ectopic pregnancy from early normal or abnormal intrauterine pregnancy can be a clinical dilemma. Pregnancy of unknown location (PUL) is a term used when a pregnancy test is positive, but ultrasound (U/S) does not show evidence of either an intrauterine or an ectopic pregnancy.
Careful evaluation of the PUL is important since ectopics represent 1% to 2% of all US pregnancies and approximately 30 to 40 women die annually in the United States from ectopic pregnancy-associated hemorrhage.1,2 Although the rate of death associated with ectopic pregnancy has declined in recent years, there are still racial disparities in mortality that may be associated with lack of access to healthcare.2,3 Thus, careful evaluation of this ED patient is warranted.
Sensitive urine tests will detect pregnancies well before they are visible on U/S. Therefore, PUL has become a frequent diagnosis. A recent consensus statement highlighted regional differences in use of the terminology and argued for more consistent uniform classification.4 That summary emphasized that PUL is an initial descriptive term that should eventually result in a final diagnosis of one of the following: ectopic pregnancy, intrauterine pregnancy (IUP), resolved PUL, or treated PUL. Accurate classification is important in research settings in order to standardize result reporting. In clinical practice it is essential in guiding appropriate treatment.
Judging the duration of pregnancy guides the clinician’s interpretation of laboratory and imaging studies. Historical factors can be helpful in assessing gestational age; however, accuracy of recollection of LMP is not consistent. A recent study looking at women seeking elective abortion found that women underestimated gestational age by 1.2 weeks, and that greater gestational age was associated with more inaccuracy.5 Other studies have shown that LMP overestimates gestational age and that accuracy of recall declines with duration since LMP.6-8 A sometimes-overlooked factor in assessing duration of pregnancy is the patient’s sexual history and self-perceived estimate of when conception occurred.
Although this patient presented without knowledge of being pregnant, women often perform pregnancy tests at home before presenting with complaints. Unfortunately, although over-the-counter tests are advertised as being able to diagnose pregnancy before a missed menstrual period, their accuracy has not been consistent in comparative trials.9-11 Despite this, taking a careful history of when the first positive pregnancy test occurred, clarifying its results, and determining whether negative pregnancy tests predated the positive test can sometimes help to narrow down gestational age.
At this point in the evaluation, this patient can be described as having a PUL. It is not a definitive diagnosis, but rather a description that should help guide evaluation that will result in a more specific diagnosis. PUL is not meant to describe the patient with presumed ectopic pregnancy based on U/S findings of a suspicious adnexal mass, nor does it include a patient in whom a sac-like structure without yolk sac is visualized (a suspected IUP). A PUL can represent a nonvisualized ectopic pregnancy, an abnormal IUP, or an early normal IUP. Distinguishing among these entities is sometimes a clinical challenge.
An important concept in evaluating a patient in this situation is the discriminatory value. This refers to the value of beta human chorionic gonadotropin (hCG) above which U/S should be diagnostic of an IUP. The discriminatory value is both user- and equipment-dependent. It should be considered a relative concept.12 Uterine malposition or malformation, the presence of fibroids, and patient obesity can all affect the quality of imaging. Most algorithms in use suggest that, if a normal IUP is present, it would be detected on U/S when the hCG level is 2000 or more.13 This assumes a singleton IUP. In multiple gestations, the hCG will be higher at any particular point in gestation. Moreover, in an early loss of a twin, the hCG could plateau and then rise.
Additionally, a recently published analysis of one center’s experience described a patient with hCG of 2317 with no IUP visualization who went on to develop a normal pregnancy. The authors modeled the association of hCG and visualization of the gestational sac and found the probability of detecting a sac would be 99% at a beta of 3510, suggesting that the discriminatory value in their institution may be higher and that the concept should be used cautiously.14 An accurate assessment of gestational age based on dates is a better predictor of U/S landmarks than is a single measurement of hCG. In the stable patient with an hCG below the discriminatory value, serial hCG follow-up may be useful in evaluation of a PUL.
Initial work by Kadar suggested that a rise of 66% should be expected over 48 hours.15 Subsequent studies have identified a somewhat lower rate of rise-53%-as compatible with normal pregnancy. Use of hCG levels must always be in the context of the clinical situation. Because patients typically do not have levels drawn at exactly 48-hour intervals and assays may differ among labs, where and when the studies were done must be noted. For these reasons, an hCG level rising at a borderline normal rate in an asymptomatic patient often warrants testing on a third occasion to get a clear indication of the trend.
If a level plateaus, drops, or is not rising appropriately, then the pregnancy is abnormal, but not necessarily extrauterine. Uterine evacuation with pathology evaluation can be diagnostic of a failed IUP if chorionic villi are found. Alternatively, it may be suggestive of an ectopic pregnancy if no villi are identified and the hCG fails to drop appropriately (at least 20% at 24 hours) following a dilation and curettage. An appropriate rise does not exclude ectopic pregnancy, as 10% to 20% will exhibit normal rises, especially at low titers.16 A patient such as this should be followed closely and undergo repeat U/S examination when the hCG reaches the discriminatory zone. Published algorithms are useful in assisting the clinician to come to a timely diagnosis.13
Progesterone levels have also been used to evaluate PUL. Initially, it was felt that a progesterone level of <5 ng/mL was likely to indicate an abnormal pregnancy. However, there are reported cases of viable pregnancies with progesterone lower than this level and ectopic pregnancies with normal progesterone levels. Moreover, the availability of the assay is not immediate, and thus a progesterone level is of limited clinical use.
Ultrasound of a symptomatic patient in early pregnancy requires careful examination of not only the endometrial cavity, but also the adnexa. The sensitivity of U/S in detecting ectopic pregnancy is dependent upon the skill of the sonographer. Its positive predictive value will depend upon the underlying likelihood of an ectopic pregnancy in the population being evaluated.
A recent study reported one center’s experience using transvaginal U/S performed by residents in obstetrics and gynecology. In patients presenting with symptoms who were eventually diagnosed as having ectopic pregnancies, 61% had nondiagnostic U/S.17 In contrast, in an early pregnancy unit with specialized sonographers, an initial U/S was able to detect 74% of ectopic pregnancies with 99% specificity.18
Endometrial thickness cannot differentiate ectopic pregnancy from either viable or nonviable IUP.19 The presence of free fluid in the posterior cul-de-sac is also not diagnostic of ectopic pregnancy. However, it may be caused by rupture or bleeding of the fallopian tube. A subjective assessment of the amount of fluid and whether it appears clear or echogenic can guide the clinician regarding the likelihood of hemoperitoneum20 (Figure 2).
In the case of suspected or obvious rupture, surgical intervention using the laparoscopic approach is warranted. In cases of hemodynamic instability, laparotomy is indicated. The decision to perform salpingectomy or salpingostomy is initially based on feasibility of the more conservative approach. If the tube is badly damaged or has been the site of a previous ectopic pregnancy, it should be removed. If unruptured, as in this case, salpingostomy can be considered. Expert opinion suggests that in the presence of a diseased or absent contralateral tube, salpingostomy is the preferred approach to maximize the potential for future fertility. Controversy has surrounded the choice between salpingostomy and salpingectomy in the patient with a normal contralateral tube. This debate centers on future reproductive outcome, including both fertility and risk of recurrent ectopic pregnancy.
A recent population-based study prospectively examined the cumulative rates of IUP for women who had undergone ectopic treatment.21 In multivariate analysis, there was no difference in fertility among women who underwent salpingectomy, salpingostomy, or medical treatment. Moreover, the rate of repeat ectopic pregnancy did not differ. However, a subgroup of women who were 35 or older with a history of infertility or tubal disease seemed to benefit from conservative surgery. Prior research has also failed to clearly favor 1 approach more than the other.22 A major disadvantage of salpingostomy is the risk of persistent ectopic tissue. Ten percent to 15% of patients will require additional medical or surgical treatment.23
In a patient with an unruptured ectopic pregnancy, the alternatives to surgical management are medical and expectant management. The clinician must ensure that methotrexate is not inappropriately administered to women with normal early pregnancies, such as an early IUP with a beta hCG below the discriminatory zone or an early pregnancy with hCG rise on the borderline of normal. Medical management with methotrexate was first introduced in the 1980s based on experience with treatment of gestational trophoblastic disease. It is now widely used. The American College of Obstetricians and Gynecologists (ACOG) reviewed use of methotrexate in a 2008 practice bulletin that was reaffirmed in 2012.24 In these guidelines, a gestational sac greater than 3.5 cm or the presence of fetal cardiac activity are considered relative contraindications to methotrexate. Studies have also demonstrated that a high pretreatment hCG level is a marker for potential failure.25 ACOG recommends considering multidose regimens for women with hCG levels higher than 5000.24
Expectant management is sometimes appropriate in asymptomatic women. ACOG suggests this can be considered in women with initial low and dropping hCG levels.24 A recent randomized trial compared expectant management to single-dose methotrexate in women with ectopic pregnancies (defined as either positive findings on U/S with plateaued hCG less than 1500 or a PUL with plateaued hCG less than 200026). Sixty percent of women in the expectant management group and 76% of those in the methotrexate group required no additional treatment. Two percent of the methotrexate group and 13% of the expectant management group required surgery. Another less-rigorously designed trial evaluated a cohort of women treated for ectopic pregnancy.27 In that study, 49% of women managed expectantly did not require other treatment. An ongoing trial is randomizing women to either methotrexate or placebo.28
Patients treated with salpingostomy, methotrexate, or expectant management all need careful follow-up because of the potential for persistent growth of trophoblastic tissue and risk of tubal rupture. The hCG is expected to drop by 15% between days 4 and 7 after methotrexate is administered. Patients who have received methotrexate and those who have undergone salpingostomy should be followed weekly until resolution. Surveillance of those managed expectantly is generally more frequent in the initial week, with repeat hCG levels every 2 to
4 days and then weekly.
In recommending treatment options, the need for frequent follow-up should be considered carefully in light of the patient’s individual circumstances. Two reports in the literature examined compliance with follow-up in inner-city populations. One found that only 10% of patients completely complied and 15% were lost to follow-up despite rigorous attempts to reach them.29 The other study had an 11% complete loss to follow-up. Only 45% were followed to the point of a negative hCG.30 Women with demonstrated noncompliance or lack of ready access to care may be better served by salpingectomy.
PULs are statistically more likely to be intrauterine than ectopic. However, ectopic pregnancy can be a life-threatening condition. Careful attention to patient history, with judicious use of U/S and hCG levels, should guide diagnosis. Once ectopic pregnancy is diagnosed, treatment options should be considered carefully, taking into account the patient’s reproductive plans and ability to comply with follow-up.
1. Centers for Disease Control and Prevention (CDC). Ectopic pregnancy mortality-Florida, 2009-2010. MMWR Morb Mortal Wkly Rep. 2012;61(6):106-109.
2. Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance-United States, 1991-1999. MMWRSurveill Summ. 2003;52(2);1-8.
3. Creanga AA, Shapiro-Mendoza CK, Bish CL, Zane S, Berg CJ, Callaghan WM. Trends in ectopic pregnancy mortality in the United States: 1980-2007. Obstet Gynecol. 2011;117(4):837-843.
4. 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(3):857-866.
5. Norman WV, Bergunder J, Eccles L. Accuracy of gestational age estimated by menstrual dating in women seeking abortion beyond nine weeks. J Obstet Gynaecol Can. 2011;33(3):252-257.
6. Blanchard K, Cooper D, Dickson K, et al. Comparison of women’s, providers’ and ultrasound assessments of pregnancy duration among termination of pregnancy clients in South Africa. BJOG. 2007;114(5):569-575.
7. Wegienka G, Baird DD. A comparison of recalled date of last menstrual period with prospectively recorded dates. J Womens Health (Larchmt). 2005;14(3):248-252.
8. Savitz DA, Terry JW Jr, Dole N, Thorp JM Jr, Siega-Riz AM, Herring AH. Comparison of pregnancy dating by last menstrual period, ultrasound scanning, and their combination. Am J Obstet Gynecol. 2002;187(6):1660-1666.
9. Ept Pregnancy Test. INSIGHT Pharmaceuticals Web site. http://www.errorprooftest.com/products/ept-pregnancy-test. Accessed February 11, 2013.
10. Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy tests at the time of missed menses. Am J Obstet Gynecol. 2004;190(1):100-105.
11. Cole LA. The utility of six over-the-counter (home) pregnancy tests. Clin Chem Lab Med. 2011;49(8):1317-1322.
12. Condous G, Kirk E, Lu C, et al. Diagnostic accuracy of varying discriminatory zones for the prediction of ectopic pregnancy in women with pregnancy of unknown location. Ultrasound Obstet Gynecol. 2005;26(7):770-775.
13. van Mello NM, Mol F, Ankum WM, Mol BW, van der Veen F, Hajenius PJ. Ectopic pregnancy: how the diagnostic and therapeutic management has changed. Fertil Steril. 2012;98(5):1066-1073.
14. Connolly A, Ryan DH, Stuebe AM, Wolfe HM. Reevaluation of discriminatory and threshold levels for serum ï¢-hCG in early pregnancy. Obstet Gynecol. 2013;121(1):65-70.
15. Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstet Gynecol. 1981;58(2):162-166.
16. Seeber BE. What serial hCG can tell you, and cannot tell you, about an early pregnancy. Fertil Steril. 2012;98(5):1074-1077.
17. Chung K, Chandavarkar U, Opper N, Barnhart K. Reevaluating the role of dilation and curettage in the diagnosis of pregnancy of unknown location. Fert Steril. 2011;96(3):659-662.
18. Kirk E, Papageorghiou AT, Condous G, Tan L, Bora S,
Bourne T. The diagnostic effectiveness of an initial transvaginal scan in detecting ectopic pregnancy. Hum Reprod. 2007; 22(11):2824-2828.
19. Kirk E. Ultrasound in the diagnosis of ectopic pregnancy. Clin Obstet Gynecol. 2012;55(2):395-401.
20. Dart R, McLean SA, Dart L. Isolated fluid in the cul-de-sac: how well does it predict ectopic pregnancy? Am J Emerg Med. 2002;20(1):1-4.
21. de Bennetot M, Rabischong B, Aublet-Cuvelier B, et al. Fertility after tubal ectopic pregnancy: results of a population-based study. Fertil Steril. 2012;98(5):1271-1276.
22. Juneau C, Bates GW. Reproductive outcomes after medical and surgical management of ectopic pregnancy. Clin Obstet Gynecol. 2012;55(2):455-460.
23. Lund CO, Nilas L, Bangsgaard N, Ottesen B. Persistent ectopic pregnancy after linear salpingotomy: a non-predictable complication to conservative surgery for tubal gestation. Acta Obstet Gynecol Scand. 2002;81(11):1053-1059.
24. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 94: medical management of ectopic pregnancy. Obstet Gynecol. 2008;111(6):1479-1485.
25. Bachman EA, Barnhart K. Medical management of ectopic pregnancy: a comparison of regimens. Clin Obstet Gynecol. 2012;55(2):440-447.
26. van Mello NM, Mol F, Verhoeve HR, et al. Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison. Hum Reprod. 2013;28(1):60-67.
27. Rodriques SP, de Burlet KJ, Hiemstra E, et al. Ectopic pregnancy: when is expectant management safe? Gynecol Surg. 2012;9(4):421-426.
28. Casikar I, Lu C, Reid S, et al. Methotrexate vs placebo in early tubal ectopic pregnancy: a multi-centre double-blind randomised trial. Rev Recent Clin Trials. 2012;7(3):238-243.
29. Dueñas-Garcia OF, Young C, Mikhail M, Salafia C. Compliance with follow-up in an inner-city population treated with intramuscular methotrexate for suspected ectopic pregnancy. Int J Gynecol Obstet. 2013;120(3):254-256.
30. Jaspan D, Giraldo-Isaza M, Dandolu V, Cohen AW. Compliance with methotrexate therapy for presumed ectopic in an inner-city population. Fertil Steril. 2010;94(3):1122-1124.
Dr. Keder is the division director of the General Obstetrics and Gynecology Division and associate professor of obstetrics and gynecology in the Department of Obstetrics and Gynecology at the Ohio State University Wexner Medical Center. She has no conflict of interest to disclose with respect to the content of this article.