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International Journal of Gynecology and Obstetrics 86 (2004) 351–357 Human chorionic gonadotrophin and progesterone levels in G. Condousa,*, C. Lub, S.V. Van Huffelb, D. Timmermanc, T. Bournea Pregnancy, Gynaecological Ultrasound and MAS Unit, Department of Obstetrics & Gynaecology, St George’s Hospital Medical School, Cranmere Terrace, London SW17 0RE, UK of Electrical Engineering (ESAT), K.U.Leuven, Belgium of Obstetrics and Gynaecology, University Hospital Gasthuisberg, K.U.Leuven, Belgium Received 26 January 2004; received in revised form 12 April 2004; accepted 12 April 2004 Abstract
Objective: To evaluate accuracy, user variability and impact of experience on the use of serum hCG and progesterone in women who have a pregnancy of unknown location (PUL’s). Materials and methods: This was a retrospectivestudy. Presenting 1932 consecutive women to an Early Pregnancy Unit had a transvaginal scan. The location of thepregnancy could not be found in 189women (Pregnancy of unknown location, PUL), and so blood was taken tomeasure serum hCG and progesterone at presentation and subsequently after 48 h, according to the protocol. Allwomen were monitored at regular intervals until the final outcome was known, which was a failing PUL, a viable orfailing intra-uterine pregnancy, an ectopic pregnancy or a persisting PUL. The final study group comprised 185 PUL,as four cases of persisting PUL were treated and excluded from the analysis. Five investigators assessed the hormonaldata independently. The investigator’s experience as defined by the number of years working in obstetrics andgynecology ranged from 2 to 15 years. Each investigator knew the women were clinically stable and that the scanresult was consistent with a PUL, i.e. there were no signs of intra- or extra-uterine pregnancy, and there was nohemoperitoneum on TVS. When assessing the PUL’s, each investigator was given the hormonal results at time 0 and48 h for serum hCG and progesterone and asked to classify the PUL’s as failing PUL’s, immediately viable intra-uterine PUL’s and ectopic PUL’s. No other clinical information about the women was made available. Results:Complete data 185 women (89%): 102 failing PUL’s, 63 immediately viable intra-uterine PUL’s and 20 ectopicPUL’s (total 185). The most experienced investigator obtained the best accuracy 163y185 (88.1%); not significantlydifferent from those obtained by less experienced investigators (range 85.9–87.6%). Mean correct classification offailing PUL and immediately viable intra-uterine PUL’s was 93% (range 89–95%); corresponding value for ectopicPUL’s was 42% (range 25–60%). Agreement between observers for classification of failing PUL’s and immediatelyviable intra-uterine PUL’s was almost perfect (Cohen’s kappa 0.86–0.90), whereas the value for ectopic PUL’s groupwas fair to moderate (Cohen’s kappa 0.39–0.67). All 5 investigators misdiagnosed same 35% of ectopic PUL’s.
Conclusions: Serum hCG and progesterone levels at defined times can be used to predict the immediate viability of *Corresponding author. Tel.: q44-208-725-0050; fax: q44-208-725-0094.
E-mail address: (G. Condous).
0020-7292/04/$30.00 ᮊ 2004 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rightsreserved.
doi:10.1016/j.ijgo.2004.04.004 G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357 a PUL, but cannot be used reliably to predict its location. Clinical experience does not significantly improve theability to assess PUL outcome.
ᮊ 2004 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Ectopic pregnancy; Human chorionic gonadotrophin; Progesterone; Interuser variability; Transvaginal sonography;Pregnancy of unknown location 1. Introduction
in 8–31% of women who present to an EarlyPregnancy Unit (EPU) The diagnosis of ectopic pregnancy should be Traditionally the discriminatory zone or level of based on the positive visualization of an extra- serum hCG above which an intra-uterine pregnan- uterine pregnancy outside the uterus, rather than cy should be visualized has been used to predict the absence of an intrauterine pregnancy. Between the likelihood of an ectopic pregnancy in women 87 and 93% of ectopic pregnancies may be visu- alized using transvaginal sonography (TVS) over a 48 h period is also utilized to predict the Standard algorithms for the diagnosis of ectopic pregnancy in the absence of the positive visuali- ments of serum progesterone have been shown to zation of an extra-uterine pregnancy utilize serum be useful in evaluating the chances of early preg- hCG and progesterone measurements with ancil- nancy failure. According to previously published lary aids that include ultrasound imaging, laparos- data, a baseline serum progesterone level of -20 copy and diagnostic dilatation and curettage. In nmolyl can be used to identify a failing PUL with our unit we rely primarily on ultrasound, with 90.8% of ectopic pregnancies visualized using are ectopic pregnancies and it is the detection of transvaginal sonography (TVS) prior to surgery women in this group that poses the greatest chal- This means that only a few ectopic pregnan- lenge. To our knowledge there are no data to cies will fall into the pregnancy of unknown examine interuser variation of the interpretation of location (PUL) category. It is this group that we these hormonal indices and observer experience on the accurate classification of PUL. Hence the With the introduction of Early Pregnancy Units objective of our study was to evaluate the accuracy, and the use of high-resolution transvaginal probes, interuser variation and impact of clinical experi- ectopic pregnancies are detected at a relatively ence on the interpretation of measurements of asymptomatic stage and more treatment options serum hormones for the assessment of women have become available. However, as women have been encouraged to present earlier in pregnancy,the number of women presenting where a pregnan- 2. Materials and methods
cy is not seen either inside or outside the uterushas increased. These cases are classified as preg- Presenting 1932 consecutive women presenting nancies of unknown location (PUL). The estab- to the EPU at St George’s Hospital, London lished hormonal criteria for the diagnosis of between June 2001 and March 2002 were studied.
ectopic pregnancy have been based on data col- All women had a transvaginal scan with a 5 MHz lected from pregnancies associated with abdominal probe (Aloka SSD 900 or 2000, Keymed Ltd., pain and abnormal transvaginal bleeding and not Southend, UK and Aloka Co. Ltd., Tokyo, Japan).
from relatively asymptomatic women. Consequent- The location of the pregnancy could not be ly new diagnostic criteria are being developed and found in 189women, and so blood was taken to tested in order to detect ectopic pregnancies in measure serum human chorionic gonadotrophin women with a PUL whilst avoiding intervention (hCG, World Health Organization, Third Interna- in early intra-uterine pregnancies. A PUL is found tional Reference Preparation 75y537) and proges- G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357 terone (Roche Elecsys 2010 Progesterone II test) was a high index of suspicion based on sympto- levels using an automated electrochemiluminesc- matology, clinical findings and sub-optimal rises ence immunoassay (‘ECLIA’). These samples of serial serum hCG levels, a laparoscopy was were measured at presentation and subsequently performed with or without an evacuation of the after 48 h, according to the protocol.
uterus. Those women who had negative findings A PUL was defined on the basis of a serum on TVS and negative findings on laparoscopy, but hCG level )5 Uyl and the absence of signs of their serum hCG levels had reached a plateau were either an intra- or extra-uterine pregnancy or given methotrexate. All women were followed up retained products of conception by TVS. All wom- until a final diagnosis was established.
en were monitored at regular intervals until thefinal outcome was known, which was a failing 3. Study design
PUL, a viable or failing intra-uterine pregnancy,an ectopic pregnancy or a persisting PUL. The The study was retrospective. Five investigators final study group comprised 185 PUL, as four assessed the hormonal data independently. The cases of persisting PUL were treated and excluded investigator’s experience as defined by the number of years working in obstetrics and gynecology Indications for sonography included non-specif- ranged from 2 to 15 years. Each investigator knew ic lower abdominal pain, with or without vaginal the women were clinically stable and had a scan bleeding, poor obstetric history (previous miscar- result consistent with a PUL, i.e. there were no riage or ectopic pregnancy) or to determine ges- signs of intra- or extra-uterine pregnancy, and there was no haemoperitoneum on TVS. When assessing the PUL, each investigator was given the hormonal made in the following way. If the initial serum results at time 0 and 48 h for serum hCG and progesterone level was -20 nmolyl, the women progesterone. No other clinical information about were classified as having a failing PUL. Sponta- neous resolution of the pregnancy was defined as Each investigator used accepted current criteria a decrease in the serum hCG level to -5 Uyl for the prediction of failing PUL, immediately with the disappearance of symptoms. The location viable intra-uterine PUL and ectopic PUL. A low of these failing pregnancies remained unknown.
serum progesterone at time 0 h was used to predict Serum hCG levels were repeated within 7 days to failing PUL’s; a serum hCG rise G66% over 48 h was used to predict immediately viable intra- If the serum hCG rise over the 48 h period was uterine PUL’s; and either a discriminatory zone G66%, for the purposes of this study, the women G1500 Uyl andyor a sub-optimally rising serum were considered to have an immediately viable hCG over 48 h was used to predict ectopic PUL’s.
intra-uterine PUL and were rescanned 2 weeks Each investigator was asked to apply these algo- later to confirm the diagnosis. When a gestation rithms to the raw hormonal data as they would in sac was seen, a further scan was performed 2 normal clinical practice. The investigators were weeks later to confirm the presence or absence of blind to the final classification of the PUL and the fetal cardiac activity. Those with no cardiac activity at the rescan were defined as being non-viablepregnancies.
Women who did not fall into either category were reviewed every 48 h until a diagnosis was Accuracy was defined as the sum of the cor- made by sonography. If an EP was visualized on rectly diagnosed ectopic PUL’s, failing PUL’s and TVS, the women were counselled appropriately immediately viable intra-uterine PUL’s divided by and offered either expectant management, medical the total number of cases studied (ns185), management in the form of parenteral methotrexate expressed as a percentage. The interuser agreement or surgery. If an EP was not visualized, but there was evaluated with kappa statistics, which give G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357 the chance-corrected measures of agreement. A Agreements between observer A and observers B–E kappa statistic of 1.0 suggests complete agreement.
Kappa statistics of 0.81–1.0 indicate almost perfect agreement, 0.61–0.8 substantial agreement, 0.41– 0.6 moderate agreement and 0.21–0.4 fair agree- ment. A kappa statistic of 0 suggests that the same degree of agreement would be expected by chance alone Cohen’s kappa was used to analyze the agreement between two observers The mod-ified method of Fleiss was used to assess the Failing PUL’s and immediately viable intra-uterine PUL’s agreement among multiple observers at the one computed individually for each PUL subclass and an overall composite kappa statistic across allsubclasses. A P value of less than 0.05 wasregarded as significant. Statistical analysis was high for failing PUL’s (93.4%, range 89.2–99%) performed using the SAS software package, ver- (90.8%, range 87.3–93.7%). Conversely, the meanaccuracy for the classification of ectopic PUL’s 4. Results
was poor by all observers (42%, range 25–60)(see .
The final clinical outcome for the 185 PUL were: 165 non-ectopic pregnancies (102 failingPUL (55.1%) and 63 intrauterine pregnancies (34.1%) and 20 ectopic pregnancies (10.8%).
observer (A) was compared to the other observers Of the 63 immediately viable intra-uterine preg- nancies, 51 were viable and 12 were non-viable observer A and the others for the diagnosis of non-ectopic PUL’s is shown in Similarlythe agreement between observer A and the others 4.2. Diagnostic accuracy of different observers for the diagnosis of ectopic PUL’s is shown inThere was almost perfect agreement The most experienced observer (A) obtained an between observer A and the other observers in the overall accuracy of 88.1%, but this value was not classification of the group containing failing PUL’s significantly different from the other observers and immediately viable intra-uterine PUL’s (Coh- (range 85.9–87.6%). The mean classification of en’s kappa 0.858–0.899). This finding is in con- non-ectopic pregnancies by all observers was very trast to the classification of the ectopic PUL group, Table 1Diagnostic accuracy of each observer G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357 whether interpretation of recorded serum hCG and progesterone levels could be used to classify PULas ectopic PUL’s or failing PUL’s or immediately viable intra-uterine PUL’s. In women with a PUL these are the criteria on which management is based. A further aim was to evaluate the influence of experience on overall test performance.
Gestational age and endometrial thickness have not been shown to be useful in the diagnosis ofectopic pregnancy in women with a PUL in which there was only fair to substantial agree- Thus, in this study, the investigators were not ment between the observers (Cohen’s kappa provided with additional demographic or ultrason- 0.394–0.672). In 75.1% of PUL all five observers made a correct classification. However, whilst all According to our data, current algorithms for five correctly classified 88.3% of failing PUL’s the diagnosis of failing PUL’s (low initial serum and 80.7% of immediately viable intra-uterine progesterone) and immediately viable intrauterine PUL’s, in no cases of ectopic pregnancy did all PUL’s (‘doubling’ serum hCG) are extremely acc- five observers agree. In 4.9% of the PUL, all five urate. The almost perfect interuser agreement in observers made an incorrect classification. In 35% the non-ectopic pregnancy group probably means of ectopic PUL’s all five observers missed the that most cases of failing PUL and immediately viable intra-uterine PUL’s are in fact quite easy to Similar information was also given by the kappa characterize on the basis of serum hormone levels.
statistics for agreement among multiple observers.
Conversely, a discriminatory zone )1500 Uyl andyor sub-optimally rising serum hCG levels for classes assigned by each observer and the kappa the diagnosis of ectopic PUL’s are poor diagnostic statistics for individual and overall PUL subclass- tests. The fair to substantial agreement between es. Kappa statistics were highest (0.861 and 0.892) the observers demonstrates the difficulty in clas- for the high-frequency subclasses of failing PUL’s sifying the ectopic group of PUL’s. This highlights and immediately viable intra-uterine PUL’s. The the need for improved diagnostic tests for the kappa statistic for the low-frequency category of If we consider the ectopic PUL group (20y185, 10.8%), which pose the greatest threat to women 5. Discussion
in the first trimester, the results are in fact quitediscouraging. All clinicians failed to diagnose The distinction between PUL’s that are devel- ectopic PUL’s in a high percentage of cases. On oping ectopic pregnancies, early intra-uterine preg- average, 58% (range 40–75%) of the women with nancies and failing PUL’s based on the inter- early ectopic PUL’s were misclassified as failing pretation of hormonal markers is the most difficult PUL and would have been managed inappropriate- diagnostic problem seen in Early Pregnancy Units (EPU). Although the vast majority will be failing The ectopic PUL’s were misclassified in the PUL’s and early intra-uterine pregnancies, it is the following way. Observer A classified 45% of the group of women with an early ectopic pregnancy ectopic PUL’s as failing PUL and 15% as imme- (approx. 10%) too early to visualize that pose the diately viable intra-uterine PUL’s. Observer B greatest concern To date, there are no pub- classified 55% of the ectopic PUL’s as failing lished data examining interuser variation of the PUL and 20% as immediately viable intra-uterine interpretation of hormonal indices and observer PUL’s. Observer C classified 35% of the ectopic experience on the accurate classification of PUL.
PUL’s as failing PUL and 5% as immediately The primary aim of this study was to assess viable intra-uterine PUL’s. Observer D classified G. Condous et al. / International Journal of Gynecology and Obstetrics 86 (2004) 351–357 30% of the ectopic PUL’s as failing PUL and 10% Acknowledgments
as immediately viable intra-uterine PUL’s. Observ-er E classified 70% of the ectopic PUL’s as failing This research was supported by interdisciplinary PUL and 5% as immediately viable intra-uterine research grants of the research council of the PUL’s. The majority of ectopic PUL’s were mis- Katholieke Universiteit Leuven, Belgium (IDOy classified as failing PUL’s. This is not surprising 99y03 and IDOy02y009projects), by the Belgian as 10y20 ectopic PUL’s had initial serum proges- Programme on Interuniversity Poles of Attraction terone -20 nmolyl. This misclassification is a (IUAP Phase V-22) and the Concerted Action potential clinical problem as seven is this group Project MEFISTO-666 of the Flemish Community.
required surgical intervention. Although the pres- Chuan Lu is supported by a KU Leuven Ph.D.
ent report is of a retrospective analysis, it high- lights the need for the development of newermodels that are not only well accepted universally, References
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Epilepsy and anti-malarial medication

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