Abstract
A pregnancy of unknown location (PUL) is a descriptive term used to classify a woman when she has a positive pregnancy test but no intra- or extra-uterine pregnancy is visualized on transvaginal sonography. Expectant management has been shown to be safe for the majority of women with a PUL. Serum progesterone and human chorionic gonadotrophin levels as well as mathematical models play a role in predicting the final outcomes of PULs, which include intrauterine pregnancy, failing PUL and ectopic pregnancy. Other possible predictors of outcome have been studied, but currently no factor has been identified that combines accuracy with reproducibility and simplicity. This article discusses the various aspects of the management of women with PULs. Future work should be aimed at prospectively testing current models in order to predict the outcome of a PUL and minimizing follow-up.
Keywords
A pregnancy of unknown location (PUL) is when, in a woman with a positive pregnancy test, an empty uterus is visualized on transvaginal ultrasound scan (TVS), with no signs of an intrauterine pregnancy (IUP) or an extra-uterine (ectopic) pregnancy. Whilst the majority of women will subsequently be diagnosed with spontaneously resolving pregnancies (failing PULs) or IUPs that were too early to visualize on TVS, a proportion will be diagnosed with ectopic pregnancies that were too early to visualize or were missed on the initial TVS examination [1,2]. The failing PUL group will include both failing IUP and extrauterine pregnancies, since the location of the pregnancy may never be determined. The definitive diagnosis of a woman with either a failed IUP or ectopic pregnancy has important clinical consequences, including prognosis as to the possibility of a repeat ectopic pregnancy, the need for assisted reproductive technologies or workup for potential recurrent pregnancy loss. Therefore, attempts should be made to make a definitive diagnosis when possible. A small group of women will have a persisting PUL, defined as PULs that biochemically behave as ectopic pregnancies. The serum human chorionic gonadotrophin (hCG) levels fail to decline and no evidence of the pregnancy is ever identified by TVS or laparoscopy [2]. PULs form a significant amount of the workload and risk associated with patients attending a hospital with complications in early pregnancy.
Studies report that in women attending an early pregnancy unit (EPU) with a positive urinary pregnancy test, the location of the pregnancy may be confirmed in up to 90–92% of cases on the basis of the initial TVS findings [1–3]. However, in practice, many more will initially have inconclusive scans and be classified as PULs outside specialist centers. Studies report that 8–31% of women referred for ultrasound assessment in early pregnancy may be initially classified as a PUL [1,2,4–6]. Published data demonstrate that whilst the majority of women (50–70%) will have spontaneously resolving pregnancies (failing PULs), 7–20% will subsequently be diagnosed with an ectopic pregnancy (Figure 1) [1,2,4,5,7]. A quarter of women with ectopic pregnancies will initially be classified as having a PUL [3]. A study from the EPU of a London, UK, teaching hospital demonstrated that more than 90% of ectopic pregnancies may be visualized on TVS prior to treatment, with 74% being visualized on the initial TVS [3]. However, the proportion of ectopic pregnancies in the PUL population and the proportion of all ectopic pregnancies initially classified as PULs will be higher if the quality of ultrasound assessment is poor.
Outcome of women attending early pregnancy units.
An expectant approach to the management of PULs has been demonstrated to be safe [1,4,5,7]. However, there is no consensus on what is an acceptable intervention rate in this group [8]. Currently, women with PULs are followed up with hormone measurements, repeat TVS and possible laparoscopy or uterine curettage until a diagnosis is confirmed. Table 1 summarizes some of the recently published studies on the prediction of ectopic pregnancy in the PUL population.
Published studies on the prediction of ectopic pregnancy in women with a pregnancy of unknown location.
CA 125: Cancer antigen 125; hCG: Human chorionic gonadotrophin; IU: International units; IUP: Intrauterine pregnancy; PUL: Pregnancy of unknown location; TVS: Transvaginal ultrasound scan.
Serum progesterone levels
Single serum progesterone levels have been used to predict the outcome of PULs. A serum progesterone level below 20 nmol/l has been shown to have a positive predictive value greater than 95% of predicting pregnancy failure [1]. Levels above 25 nmol/l are ‘likely to indicate’ and levels above 60 nmol/l are ‘strongly associated’ with pregnancies subsequently demonstrated to be viable [9]. However, viable IUPs have been reported with initial levels below 16 nmol/l. Serum progesterone measurements have also been advocated as a diagnostic tool in the noninvasive diagnosis of ectopic pregnancy. However, a meta-analysis of 26 studies has demonstrated that, whilst a single serum progesterone measurement has a good discriminative capacity to distinguish between pregnancy failure and a viable IUP, a single measurement cannot discriminate between ectopic pregnancy and nonectopic pregnancy [10]. This review concluded that serum progesterone measurement can identify women at risk for ectopic pregnancy who need further evaluation, but its discriminative capacity is insufficient to diagnose ectopic pregnancy with certainty. Therefore, it would appear that a serum progesterone level is good at predicting viability, but not the location of pregnancy.
Serum hCG levels
A single serum hCG measurement is used by some as a discriminatory level to help with the detection of ectopic pregnancy. The concept was initially developed with respect to trans-abdominal ultrasound examinations, when it was reported that the absence of an intrauterine gestational sac at an hCG concentration of greater than 6500 international units (IU)/l had a sensitivity of 100%, a specificity of 96%, a positive predictive value of 86% and a negative predictive value of 100% for the prediction of an ectopic pregnancy. This approach was 98% efficient, based on a 19.4% prevalence of ectopic pregnancies among the group [11]. However, a high negative predictive value for diagnosing a clinical outcome with a high prevalence does not demonstrate that the test has a high diagnostic performance.
The introduction of high-resolution TVS has led to the discriminatory hCG level being decreased. Serum hCG levels of 1000, 1500 and 2000 IU/l have been used [12,13]. However, a study on the use of varying discriminatory levels has demonstrated that using a single value of serum hCG in a PUL population is of limited value (Table 1) [13]. Many ectopic pregnancies in a PUL population have a relatively low serum hCG level, and so clinicians may be falsely reassured about the location of the pregnancy.
The change in serum hCG over time has been used to predict the outcome of PULs. Kadar et al. were the first to describe the minimal rate of increase for an IUP to be 66% over 2 days [14]. This study was based on a small sample of 20 women and used an 85% confidence interval (CI). More recently, the minimal rise in serum hCG level in viable IUPs was reported to be 53%, on the basis of a 99% CI [15]. However, in clinical practice, a more conservative cutoff of 35% has been suggested to minimize the potential risk of terminating a wanted pregnancy [16]. Serum hCG curves for expected hCG declines in spontaneous miscarriages have also been described [17]. In addition, the change in serum hCG level over 48 h has also been referred to as the ‘hCG ratio’ (hCG 48 h:hCG 0 h). An hCG ratio of less than 0.87 (or an hCG decrease >13%) has been demonstrated to have a sensitivity of 92.7% (95% CI: 85.6–96.5) and a specificity of 96.7% (95% CI: 90.0–99.1) for the prediction of a failing pregnancy [18]. There is less information on corresponding curves or rules for the behavior of serum hCG levels in ectopic pregnancies. Silva et al. recently concluded that there is no single way to characterize the pattern of serum hCG behavior in ectopic pregnancies [19]. They found that the number of women with an ectopic pregnancy who experienced an increase in hCG was approximately equal to the number who experienced a decrease. The hCG profile mimicked that of an IUP in 21% of women and that of a spontaneous miscarriage in 8% of women with an ectopic pregnancy [19]. Most investigators report a suboptimal rise in serum hCG in ectopic pregnancies, corresponding to a rise less than that expected in viable IUPs. A study investigating 196 ectopic pregnancies reported a sensitivity of 83% and a specificity of 95.4% for the detection of ectopic pregnancy, after initially excluding cases that were thought to be IUPs, defined by a serum hCG increase of more than 35% and failing pregnancies as a serum hCG decrease of more than 21–35% [16]. Of the 34 missed ectopic pregnancies in this study, 27 (80%) were mis-classified as IUPs, as were 14% of all the ectopic pregnancies. Many of the difficulties in interpreting hCG levels in ectopic pregnancies are because up to 15–20% of them have doubling serum hCG times similar to that of IUPs [19,20].
Mathematical models
Recently, mathematical models using logistic-regression and Bayesian networks have been developed in order to predict the outcome of PULs (Table 1). Two logistic-regression models (M1 and M4) have been developed to predict the outcomes of PULs, based on the results of two serum hCG levels taken at 0 and 48 h, respectively, (Table 1) [21–23]. Model M1 is based on the hCG ratio and its performance was evaluated using receiver operator characteristic (ROC) analysis. It gave an area under the ROC curve (AUC) of 0.975 for failing PUL, 0.966 for IUP and 0.885 for ectopic pregnancy. For the detection of ectopic pregnancy, it had a sensitivity of 91.7%, a specificity of 84.2%, a positive likelihood ratio of 5.8, a positive predictive value of 27.5% and a negative predictive value of 99.4% [21]. When tested in the clinical setting, this model was found to compare favorably with subjective assessment by experienced nurse operators [24]. M4 is based on the hCG average ([hCG 0 h + hCG 48 h]/2), the hCG ratio and its quadratic effect [22]. During development on a set of 376 PULs, M4 gave an AUC of 0.978 (95% CI: 0.954–1.000) for the prediction of failing PUL, 0.974 (95% CI: 0.954–0.994) for the prediction of IUP and 0.900 (95% CI: 0.812–0.988) for ectopic pregnancy [22]. This model appears superior to M1 when comparing AUCs for the prediction of ectopic pregnancy in a PUL population but, in real terms, it did not result in many more pregnancies being correctly identified as ectopic pregnancies [22]. The obvious advantage of these models is that their use is independent of clinical experience and they do not require any understanding of clinical biochemistry in early pregnancy. In a recent prospective study investigating 363 PULs, it was demonstrated that such a model can be used as a basis on which to rationalize the management of PULs, as it can successfully minimize their follow-up by reducing the number of visits, scans and blood tests, as well as intervention rates [7]. Although misclassification of the final outcome resulting in rupture of ectopic pregnancy is a possibility with the use of such mathematical models, in this prospective study there was no serious morbidity in any of the women and, specifically, no ruptured ectopic pregnancies [7]. These models may, therefore, have the potential to de-skill the interpretation of serum hCG levels and lead to more standardized management protocols. However, they need to be tested prospectively and in other patient populations.
Uterine curettage
One commonly used algorithm to diagnose ectopic pregnancy is based on the use of pelvic ultrasound to demonstrate the absence of an intrauterine sac followed by uterine curettage, after a viable pregnancy has been excluded either by a low serum progesterone level or on the basis of a suboptimal rise in hCG over 48 h [25,26]. According to this protocol, if the hCG level fails to decrease by more than 15% or increases 8–12 h after curettage, a diagnosis of ectopic pregnancy is assumed. This approach does have pitfalls as it may lead to intervention in some viable intrauterine pregnancies. A study investigating 1003 PULs has shown that criteria established for the use of uterine curettage in the management of PULs, including those advocated by the American Society for Reproductive Medicine (ASRM), could theoretically result in inadvertent termination of an ongoing IUP [27]. Uterine curettage should, therefore, not have a routine place in the management of PULs and the diagnosis of ectopic pregnancy. However, it may play a role in diagnosing the location of failing PULs, but it should not be used until the possibility of a viable pregnancy has been eliminated.
Diagnostic laparoscopy
The combination of a positive serum hCG above a discriminatory zone of 1000–2000 IU/l and an empty uterus shown by TVS is an accepted indication for diagnostic laparoscopy in many units. However, as discussed previously, using a single value of serum hCG to predict PUL outcome is of limited value [13]. Many women with ectopic pregnancies have a low serum hCG, below that used in discriminatory zones and, therefore, would not undergo laparoscopy. By contrast, some failing PULs and early IUPs have high serum hCG levels and will undergo an unnecessary laparoscopy. Indications for diagnostic laparoscopy should be dependent upon the quality of the ultrasound equipment, the experience of the sonographer, prior knowledge of the woman's risks and symptoms and the presence of physical factors, such as uterine fibroids [13].
Other markers
Other serum markers that have been examined to determine if they are predictive of pregnancy outcome in the PUL population include cancer antigen (CA) 125, creatine kinase and activin A. Maternal serum CA 125 levels peak during the first trimester of pregnancy and are thought to originate from the decidual cells affected by chorionic invasion or placental separation. CA 125 levels have previously been reported to be to be significantly lower in ectopic pregnancies compared with IUPs [28]. When CA 125 levels were incorporated into a logistic-regression model to predict the outcome of PULs, they were found to be able to distinguish failing PULs from IUPs, but were not able to detect those at risk of ectopic pregnancy [29]. Creatine kinase has been found in all smooth muscles, including the fallopian tube, and is a nonspecific marker of smooth muscle damage. It has been suggested that damage to the fallopian tube, as in the case of a tubal ectopic pregnancy, is sufficient to cause an increase in maternal creatine kinase levels [30]. However, it has been shown that creatine kinase levels cannot be used to predict the outcome of PULs [29].
More recently, serum activin A levels have been used to predict ectopic pregnancy [31]. Serum levels were found to be significantly lower in women with ectopic pregnancies compared with those with IUPs or miscarriages. Using a cutoff value of 0.37 ng/ml gave a sensitivity and specificity of 100 and 99.6%, respectively, for the prediction of ectopic pregnancy [31]. However, preliminary unpublished data from our unit on 141 women classified with a PUL do not support this finding. Serum levels of VEGF have also been shown to be higher in women with ectopic pregnancy [32,33]. Whilst VEGF levels have also been found to be elevated in IVF patients who were subsequently diagnosed with ectopic pregnancies [34], use of this marker has not yet been examined in the PUL population.
Number of visits
As previously mentioned, neither the sole use of a single progesterone level nor a single hCG measurement, as used when applying a discriminatory zone, is useful in the prediction of ectopic pregnancy in women with a PUL. A single-visit strategy based on the initial serum progesterone in combination with the initial serum hCG level to categorize women into being at either high or low risk of ectopic pregnancy has also been developed and tested prospectively on a total of 518 PULs [35]. While it correctly eliminated 84% of nonectopic pregnancies from further follow-up, its safety was challenged since 67% of ectopic pregnancies would also have been discharged without adequate follow-up. Therefore, current research suggests that more than one visit is necessary to successfully predict ectopic pregnancy within the PUL population.
Although there are strategies, such as the use of mathematical models that enable the location of the pregnancy to be predicted within 48 h, in reality, in many cases it is often significantly longer before the true location of the pregnancy is confirmed after either TVS or surgical intervention, in the form of either laparoscopy or surgical uterine evacuation. At present, there is no standardized protocol for follow-up. During this time period, women may have multiple blood tests in order to measure serum hCG and progesterone levels and undergo numerous TVS examinations until the pregnancy is visualized or hCG levels decrease. This represents a significant workload for clinicians and is inconvenient for patients.
A recently published, prospective study aimed to rationalize the follow-up of women with PULs by managing them according to a protocol based on the predictions of a mathematical model [7]. Almost 90% of the women included were successfully managed according to the set protocol, with the majority of IUPs (80.2%) being confirmed on the basis of two ultrasound scans and two serum hCG measurements within 7 days ± 1 day, and the majority of failing PULs (93.0%) being confirmed within 2 days after only one TVS examination and two serum hCG measurements. The majority of ectopic pregnancies (87%) were diagnosed within 7 days. Overall, more than 60% of PULs could be eliminated from further follow-up at 48 h. By 7 days after presentation, only 2.5% of women remained classified as PULs. Further studies are now needed to test the reproducibility of such models and follow-up protocols in other units. Seeber et al. have also demonstrated that the time to diagnosis of an ectopic pregnancy can be decreased by 2.5 days with the use of hCG curves compared with conventional clinical management [16].
Summary of consensus statement issued by the International Society of Ultrasound in Obstetrics and Gynecology on pregnancies of unknown locations.
The prevalence of pregnancies of unknown locations (PULs) is determined by the quality of ultrasound scanning.
Most PULs are not aggressive and represent either failing pregnancies or intrauterine pregnancies that are too early to visualize on transvaginal ultrasound scan.
Clinically stable women with PULs should be managed expectantly.
The initial serum human chorionic gonadotrophin (hCG) level is not predictive of pregnancy outcome.
The change in serum hCG over time (hCG ratio) and progesterone levels can be used to predict failing PULs.
Mathematical models to predict PUL outcome have been developed but need to be tested in multicenter trials.
In most cases, uterine curettage should not play a role in the classification of PULs.
A single-visit approach to the management of PULs is not appropriate.
Data taken from [8].
Future perspective
The International Society of Ultrasound in Obstetrics and Gynecology has created a consensus statement on PULs (Box 1) [22]. It states that the women with PULs should initially be managed expectantly and both biochemistry and mathematical models can be used to predict PUL outcome. However, the mathematical models need to be tested prospectively in multicenter trials. Further studies are also required to compare the use of the hCG ratio and progesterone levels in the diagnosis of failing pregnancies. In addition, further attention should be concentrated on reducing the length of follow-up required in women with a PUL. Women classified with PULs can provide a significant workload. Reducing the number of follow-up visits required and the length of follow-up would be advantageous for patients and clinical staff alike. Consideration must be given in reducing the number of PULs, since a large number of PULs merely reflects women attending for ultrasound assessment too early in pregnancy.
Executive summary
Pregnancy of unknown location (PUL) is a descriptive term rather than a pathological diagnosis.
A woman is classified as having a PUL when she has a positive pregnancy test, with no signs of an intra- or extra-uterine pregnancy on transvaginal ultrasound scan (TVS).
The term is not synonymous with ectopic pregnancy. Whilst a proportion of women will subsequently be diagnosed with an ectopic pregnancy, other final pregnancy outcomes include a failing PUL, intrauterine pregnancy and a persisting PUL.
Expectant management has been demonstrated to be safe for the majority of women classified with PULs.
Serum progesterone levels have been used to predict the outcome of PULs, but appear to be better at predicting pregnancy viability than pregnancy location.
Using a single serum human chorionic gonadotrophin (hCG) level to predict pregnancy outcome in the PUL population is of limited value.
The change in serum hCG over 48 h expressed as the hCG ratio (hCG 48 h:hCG 0 h) is helpful in predicting the outcome of PULs.
Logistic-regression models based on serum hCG levels have been developed in order to predict the outcome of PULs.
Use of the models is not operator dependent and they have the potential to lead to more standardized management protocols.
They can be used to reduce the follow-up of PULs by classification at 48 h.
Serum cancer antigen 125, creatine kinase and activin A levels have been studied as possible predictors of pregnancy outcome. However, no single factor has yet been identified to predict the outcome of PULs that combines accuracy, reproducibility and simplicity.
In most cases, uterine curettage should not play a role in the classification of PULs.
Current models to predict the outcome of PULs need to be tested prospectively in other units.
Further efforts should be concentrated on reducing the number and length of follow-up in women with PULs.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.