1 Department of Obstetrics and Gynaecology, H:S Hvidovre Hospital, University of Copenhagen, 2650 Hvidovre and 2 Department of Obstetrics and Gynaecology, H:S Frederiksberg Hospital, University of Copenhagen, 2000 Frederiksberg, Denmark
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology 537, H:S Hvidovre Hospital, University of Copenhagen, Kettegaard Alle 30, 2650 Hvidovre, Denmark. e-mail: christina.roerbye{at}hh.hosp.dk
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Abstract |
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Key words:
-hCG/diagnostic test/failure/medical abortion/prediction
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Introduction |
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Failures diagnosed after the 2 week follow-up, defined as late failures, are associated with retained products of conception and heavy or prolonged bleeding. The absolute and/or relative -hCG might therefore be higher in failures than successes, and could perhaps be an indicator of late failure. This hypothesis is supported by Honkanen et al. (2002
), who found that the decline in
-hCG after a medically induced abortion is inversely correlated with the time taken to abort. The thickness of the endometrium is a useful parameter in diagnosing incomplete abortion after first trimester spontaneous abortion (Wong et al., 2002
), and is also expected to be useful in diagnosing failure after medical abortion.
With this background, we wanted to compare the absolute and the relative -hCG values and the endometrial thickness after 12 weeks in successes and late failures after medical abortion, and to analyse the prognostic value of these variables.
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Materials and methods |
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In all, 694 women were followed-up with a clinical visit 2 weeks after the medical abortion. A transvaginal ultrasonography was performed (day 1416) on a Siemens Sonoline SI-400 or SI-200 (57 mHz) measuring the maximum thickness of the endometrium in a sagittal dimension (double-layer including tissue in the cavity). Serum -hCG was measured initially and on day 15 (day 1416). In one of the departments an additional measurement of
-hCG was performed in 133 women on day 8 (day 79). In all, 177 women were excluded due to one or more of the following reasons:
-hCG measurements on incorrect days (n = 90), performance of ultrasonography on incorrect days (n = 79) or surgical intervention before day 15 (n = 8). Late failure was defined as surgical intervention after day 15 and within 15 weeks. No interventions on women included in the study were performed as a consequence of either serum
-hCG values or ultrasonographic images.
All women were followed up by a unique personal identification number in a computer system 15 weeks after initiation of the abortion, allowing identification of all surgical interventions anywhere within the country due to abortion-related complications. No women were lost to follow-up in this study.
The median values of the different variables for late failures and successes were compared by MannWhitney U-test. The positive and negative predictive values as well as sensitivity and specificity were calculated and analysed at different threshold limits for absolute -hCG values on days 1, 8 and 15 and for relative
-hCG values on days 8 and 15, and for different endometrial thicknesses on day 15. To characterize each parameter with respect to its accuracy to detect failures, sensitivity and specificity were calculated from 2x2 contingency tables for each possible threshold value and plotted as receiver operating characteristic (ROC) curves. The areas under the curves (AUC) were calculated as a test for the hypothesis that AUC is not significantly different from 0.5, the area under the straight line (sensitivity = 1 specificity) that represents no discrimination between failure and success.
The local ethics committee approved the study, and all patients gave informed consent.
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Results |
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The absolute as well as the relative values of -hCG 12 weeks after the abortion were significantly higher in the late failure group than in the success groupwith a wide range within each group and a great overlap of values between the two groups (Figures 1 and 2). Two women had higher
-hCG values on day 8 compared with day 1, but both had successful abortions without surgical intervention. The median endometrial thickness measured by ultrasonography on day 15 was greater in the late failure than in the success group: 16 mm (1318) versus 10 mm (713) (lower and upper quartiles, P < 0.0001).
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Discussion |
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The overall percentage decline in -hCG is consistent with earlier findings (Walker et al., 2001; Honkanen et al., 2002
). Both the absolute and the relative values of
-hCG as well as the endometrial thickness after medical abortion were higher in women who turned out to be late failures than in successfully treated women. However, we conclude that none of these variables can be used as diagnostic tests in predicting late failure after medical abortion.
The demands for a diagnostic test depend on the clinical situation, the consequences of a positive test result, and the risks connected with an overlooked condition. Diagnosing a failed medical abortion leads to surgical intervention often performed under general anaesthesia. To avoid unnecessary interventions, the positive predictive value of the applied test must be high. The specificity should not be <0.95, which is the approximate chance of a successful course using this medical abortion regimen.
We found that threshold levels of -hCG and endometrial thickness with high positive predictive values had a low sensitivity, leading to identification of only a minority of the failures. As an example: using
-hCG >5000 on day 15 as a threshold, the specificity was 0.99, the positive predictive value was 0.69, but the sensitivity only 0.28. Used in a clinical situation, this means that 31% of performed interventions would be unnecessary, while 72% of the failures would be missed. Higher positive predictive values were achieved by combining changes in
-hCG and endometrial thickness, but still at the expense of sensitivity. As an example: a
-hCG value >5000 on day 8 combined with an endometrial thickness >10 mm on day 15 gave the positive predictive value 0.75, but the corresponding sensitivity was 0.28 and the specificity 1. Similar values were seen with other combinations of different threshold levels.
We found that none of the analysed parameters was acceptable as a diagnostic test because of the low positive predictive values. The consequences of overlooking a failure are limited, as the risk of serious morbidity associated with retained tissue is minimal and because failures ultimately will be revealed clinically. With this background we conclude that the analysed variables used as diagnostic tests would lead to an unacceptable number of unnecessary interventions. If a positive test result could lead to a simple, risk-free, definitive test, a higher false positive rate could be acceptable, but such a definitive test has not been proven.
Since we did not intervene on either -hCG values or on specific endometrial thicknesses, but followed the spontaneous courses after a 2 week follow-up, we were able to analyse the prognostic value of
-hCG and ultrasonography as predictors of late failure. Serum
-hCG was measured according to the internationally accepted standard reference, but the absolute values may vary with different assays. The use of relative changes allows comparison between centres using different assays. Resident doctors under the supervision of a specialist doctor performed the ultrasonography at follow-up. We have not analysed the validity of the measurements of the endometrial thickness and therefore cannot exclude a possible inter-observational discrepancy. To minimize this, all residents had to qualify before authorization was given to perform ultrasound examinations at our department. Furthermore, doctors were unaware of the final outcome. There is no reason to believe that a systematic error has been made, but rather a random incorrectness that does not influence the conclusion. Moreover, our findings are consistent with endometrial thicknesses after a tamoxifen/misoprostol regimen (Harwood et al., 2001
).
Some of the cases excluded in this study were unavoidable, because surgical intervention was performed before follow-up on day 15, but the majority of exclusions was caused by a lack of serial -hCG values or ultrasonography performed on the correct days. Similar frequencies of lost or incorrect follow-up after induced abortion are a recognized problem (Thonneau et al., 1998
). However, the baseline characteristics were similar in the women included and those women excluded, and it is therefore unlikely that results from the excluded women would affect the overall conclusion. Comparing women in the failure group with women in the success group revealed more parous women among failures, which correspond to the increased risk of failure with increased parity (Bartley et al., 2000
).
Following mifepristone administration, -hCG continues to increase, but declines precipitously after administration of misoprostol (Somell et al., 1990
; World Health Organization Task Force, 1991
; Walker et al., 2001
; Honkanen et al., 2002
). The finding of significantly higher absolute and relative
-hCG values among late failures compared with successes on days 8 and 15 after a mifepristone/prostaglandin regimen has, to our knowledge, not been published previously. The only published predictive analysis concluded that a decrease in
-hCG of <50% within 24 h after misoprostol administration in methotrexate pre-treated women was associated with an increased risk of ending as a failure, but the positive and negative predictive values were not given (Creinin, 1996
).
In conclusion, absolute and relative -hCG values as well as endometrial thickness were significantly higher in late failures than successes after medical abortion, but none of these parameters is clinically useful as a diagnostic test in predicting late failure after medical abortion.
-hCG measurement and ultrasonography can be used to identify ongoing pregnancies, and might be helpful in a clinical situation of doubt, but are merely supplements to the general clinical evaluation. After ongoing pregnancy is excluded, only the clinical course will reveal the remaining failures. The women must therefore be informed to return for a clinical examination in cases of acute or prolonged bleeding, pain or fever, as these signs may be indicators of failure or other complications that need treatment.
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Submitted on September 23, 2002; resubmitted on August 20, 2003; accepted on September 23, 2003.