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EARLY PREGNANCY: Biology and Medicine Editor-in-Chief: Eytan R. Barnea MD, FACOG

July 2000
Volume IV, Number 3
ISSN: 1537-6583
Pages: 203-213

Ultrasonographic Criteria For Non-Viability Of First Trimester Intra-Uterine Pregnancy

Mariette H. Schouwink^{* †}, Bianca F. Fong^*, Ben W.J. Mol^{* ‡}, and Fulco van der Veen^*

*Department of Obstetrics and Gynecology, ^‡Department of Clinical Epidemiology and Biostatistics Academic Medical Center, University of Amsterdam, The Netherlands

Running title: diagnosis of first trimester intra-uterine pregnancy

Key words: cardiac activity/ diagnosis/ intra-uterine pregnancy/ transvaginal sonography/ yolk sac

Acknowledgement: We acknowledge M.P. Burger MD PhD and W.M. Ankum M.D. PhD of the department of Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, for critical comments on an earlier draft of the manuscript.

Abstract

This prospective cohort study evaluated the performance of transvaginal sonography in the assessment of first trimester intra-uterine pregnancy. Consecutive women with singleton pregnancies who underwent a first trimester transvaginal sonographic examination between May 1995 and March 1996 were included. Women had to have an intra-uterine gestational sac and time since last menstrual period of less than 12 weeks. In case of absent cardiac activity and a crow-rump length < 12 mm, the test sonography was repeated with a 7 to 10 days interval. A final diagnosis, that was considered to be the gold standard in further analysis, was established by sonography performed one week after the last test sonography.

Among 372 pregnancies, there were 92 (25%) non-viable. The combination of absence of cardiac activity and absence of a yolk sac appeared to be a highly specific criterion whenever the mean sac diameter was ³ 16 mm or whenever a crown rump length was > 5mm. We conclude that single transvaginal sonography is a reliable test to diagnose non-viable pregnancy in case the MSD is ³ 16 mm or in case the crown rump length is > 5mm.

The combination of absence of cardiac activity and absence of a yolk sac virtually rules out the possibility of a viable pregnancy in these patients.

Introduction

In the last decade transvaginal ultrasound has proven to be more accurate than transabdominal ultrasound in the diagnosis of early pregnancy and its complications (Levi et al., 1988; Wilson et al., 1986). It allows earlier and detailed visualization of the gestational sac. The yolk sac is the first of the structures visualized inside the gestational sac in the normally developing intra-uterine pregnancy. This is followed by the embryonic pole, which can be first recognized as a thickening along the yolk sac. The primitive heart is early prominent, and cardiac activity can often be detected before the embryo itself can be distinguished from the adjacent yolk sac (Wilson et al., 1986).

For diagnostic purposes the important question is not when early cardiac activity can be visualized, but rather at what point its absence can be considered a definitive sign of early pregnancy failure. The same applies to the absence of the yolk sac in early pregnancy. In patients experiencing signs of threatened abortion, intervention can only be started when there is virtually 100% certainty about the failure of pregnancy. Therefore, diagnostic tests used in the evaluation of first trimester intra-uterine pregnancy require 100% specificity, with the highest possible sensitivity.

Various authors have evaluated transvaginal sonographic criteria that may be useful in differentiating between normal and abnormal gestations (Table I) (Levi et al., 1988; Wilson et al., 1986; Brown et al., 1990; Levi et al., 1990; Goldstein et al., 1992; Tongsong et al., 1994). As is clear from Table I, different criteria are used to distinguish viable and non-viable first trimester intra-uterine pregnancies. While some authors consider the absence or presence of a yolk sac as the most reliable predictor of the outcome of pregnancy, others rely on the absence or presence of an embryo or of cardiac activity to make an accurate decision on viability or non-viability. Furthermore, the studies use different sizes of the mean sac diameter (MSD) or crown rump length (RCL), and they describe highly selected populations, such as subfertility patients.

The reported diagnostic performance of the studied sonographic criteria vary widely, with specificities varying between 92% and 100%, and sensitivity varying between 50% and 100%. Furthermore, other studies have focussed on sonographic criteria to rule in viability (Britten et al., 1994; Coulam et al., 1996). However, for clinical practice, it is both for the information provided to the patient and for further management of imminent importance to know which sonographic findings rule out viability. The purpose of this study was therefore to evaluate the diagnostic accuracy of transvaginal sonography in the diagnosis of non-viable intra-uterine pregnancy among consecutive women, attending the outpatient clinic of an academic hospital. The sonographic criteria that were analyzed were the absence of a yolk sac, the absence of cardiac activity and the absence of both of them, at different MSDs and CRLs.

Patients And Methods

Consecutive women with singleton pregnancies who underwent a first trimester transvaginal sonographic examination between May 1995 and March 1996 at the Department of Obstetrics and Gynecology or the Infertility Clinic of the Academic Medical Center in Amsterdam were included in the study. All women had to have a single intra-uterine gestational sac and duration of pregnancy of less than 12 weeks, defined as a maximum crown-rump length (CRL) of 56 mm or a maximum biparietal diameter of 19 mm at the first examination. The clinical indications for the ultrasound examination were: previous subfertility, threatened abortion - defined as vaginal bleeding or abdominal pain -, doubtful dates and prenatal diagnostic procedures.

The gynecologists or residents performed the sonographies. There were several available transvaginal scanners: Hitachi’s EUB 415 A, EUB 515 A and EUB 565 A (Hitachi, Tokyo, Japan) with a 6.5 mHz probe, a Toshiba SSA 250 (Toshiba, Tokyo, Japan) with a 6.0 mHz probe, and an ATL-HDI 3000 (ATL, Botheel, USA) with a 5 to 9 mHz probe.

The MSD, calculated by averaging three perpendicular diameters and rounding to the next millimeter, was registered. Furthermore, the CRL was measured, presence of a yolk sac and presence of cardiac cardiac activity were registered. The data were accumulated prospectively and filled out on standardized record forms.

In case of absent cardiac activity and a MSD < 12 mm, sonographies were repeated with 7 to 10 days intervals, until cardiac activity appeared or until there was no more growth of the MSD. One week after the last test sonography, a reference sonography was performed, that was considered to be the ‘gold standard’. Viable pregnancies were those in which cardiac activity was present at the reference sonography. Non-viable pregnancies were those in which cardiac activity was absent on the reference sonography. In case spontaneous abortion occurred before the reference sonography was performed, the pregnancy was considered to be non-viable. The profile of patients lost to follow-up was compared with the profile of patients in which follow-up was known. A P-value < 0.05 was considered to indicate statistical significance.

We analyzed the diagnostic accuracy of the absence of cardiac activity, the absence of a yolk sac, and the absence of both the yolk sac and cardiac activity. Absence of a yolk sac, absence of cardiac activity and absence of both of them were considered positive test results, i.e. a non-viable pregnancy. Two by two tables were constructed, in which the results of the first test sonography were compared with those of the reference sonography. Multiple tables were made for each test at different values of the MSD and CRL (Table II). The sensitivity of a test was calculated by dividing the number of non-viable pregnancies detected with this test by the total number of non-viable pregnancies. The specificity of a test was calculated by dividing the number of viable pregnancies detected with this test by the total number of viable pregnancies in our study. Subsequently, two by two tables were constructed comparing the last test sonography, i.e. the last sonography that was performed before the reference sonography, with the reference sonography.

To find out if other diagnostic features, i.e. abdominal pain, vaginal bleeding and the reason for referral contributed to the diagnostic process logistic regression analysis was incorporated in a model. A receiver operating characteristic (ROC)-curve was constructed to assess the performance of the model. Th area under the ROC-curve, which can be considered as a measure for the performance of a test or combination of tests, was calculated. Subsequently, other diagnostic features abdominal pain, vaginal bleeding and the reason for referral were added to the model to see whether the area under the ROC-curve improved.

When evaluating the viability of an intra-uterine pregnancy, the MSD itself can also be used as a diagnostic marker. To assess the diagnostic performance we constructed receiver-operating-characteristic (ROC) curves for MSD and for MSD corrected for gestational age. An area under the ROC-curve was calculated for both tests. The area under the ROC-curve expresses the diagnostic performance of a test. A test without any discriminative capacity has an area under the ROC-curve of 0.5, whereas a perfect test has an area under the ROC-curve of 1.

To evaluate the accuracy of MSD as a diagnostic test, we constructed ROC-curves for MSD and for MSD adjusted for gestational age. The formula that was used for the adjustment was MSD_adj = MSD – 2.37 – 2.47*(gestational age in days). This formula was obtained through linear regression analysis of the association between MSD and gestational age in the present data. An area under the ROC-curve was calculated for both MSD and MSD adjusted for gestational age

Results

Discussion

This prospective study among 372 patients shows the combination of absence of a yolk sac and absence of cardiac activity at sonography to be very specific for the diagnosis of non-viable first trimester pregnancy in case the MSD was ³16 mm or in case the CRL was ³5mm. A single sonography is insufficient to diagnose pregnancy failure with enough certainty to justify intervention in case the MSD is < 16 mm and the CRL is < 5mm.

The prospective character of our study could not prevent that 12% of our patients was lost to follow-up. The fraction of patients lost to follow up was higher after an abnormal sonography than after normal sonography, thereby implicating that we might have underestimated the sensitivity and overestimated the specificity by a mechanism known as verification bias (Begg et al., 1988). However, since this fraction was only 12% we think that this does not affect our conclusions importantly.

We studied the performance of ultrasound in a rather unselected population, in contrast to the populations in previous studies. Although the prevalence of non-viable pregnancies differed considerably between groups with various clinical indications, logistic regression analysis showed that this feature provided no clinically relevant information in addition to the findings at sonography. The overall prevalence of non-viability was as high as 25%. This due to the fact that a considerable part of the patients were included after threatened abortion, in group which the prevalence of non-viability was 52%. However, under the assumption that sensitivity and specificity are test properties that are independent from the prevalence of disease, we can calculate predictive values for different prevalences of non-viability. Assuming the incidence of non-viability to be 25%, a sensitivity of sonography of 40% with a specificity of 99.6% would results in a positive predictive value of 97% and a negative predictive value of 62%. Even an incidence of non-viable pregnancies of 15% would result in a positive predictive value of 95%.

The MSD was found to provide diagnostic information in case it was corrected for gestational age. However, it’s specificity did not exceed 95%, thereby indicating that the MSD as an independent test is not reliable enough to diagnose non-viability. Recently, Steinkampf and colleagues reported on 28 women whom ovulation had been induced (Steinkampf et al., 1997). The authors reported that 95% of the pregnancies with an MSD of 16 mm showed fetal cardiac activity at sonography. This percentage was 99% when the MSD was 19mm. In contrast with these findings, the present study shows that absence of fetal cardiac activity is not 100% specific as long as the MSD is  ³25 mm. However, combination of absence of a yolk sac and of cardiac activity is perfectly specific in case the MSD is  ³16 mm.

An issue in the diagnosis of first trimester pregnancy is whether a single transvaginal sonography can diagnose non-viability with near perfect specificity. Previous studies have focussed on the moment at which cardiac activity can be detected in normal pregnancies (Britten et al., 1994; Coulham et al., 1996). In these studies, fetal heart rate was evaluated in relation to gestational sac diameter and crown rump length. Fetal heart patterns were not incorporated in the present study, since we feel that the viability of a pregnancy can never be ruled out in the presence of cardiac activity, albeit at low rate. Furthermore, Britten and Coulham did not include abnormal pregnancies in their study, thereby ruling out the possibility to calculate the sensitivity of sonography.

Analysis of the findings of the first sonography showed specificity of a yolk sac and cardiac activity to be low when the MSD was < 16 mm. Specificity increased when the results of the last test sonography before the reference sonography were considered as the final test result. Based on this finding, we recommend repeating sonography with a 7 day interval, until the MSD is  ³16 mm or the CRL is  ³5 mm, or until cardiac activity is present. Thus, single transvaginal sonography is a very reliable test in case the MSD is  ³16 mm or in case the CRL is ³ 5 mm. The combination of absence of cardiac activity and absence of a yolk sac in these fetuses virtually rules out the possibility of a viable pregnancy in these patients. In case the MSD is < 16 mm or in case the CRL is < 5mm, sonography should be repeated in order to establish the diagnosis non-viable pregnancy.

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References

Begg, C.B.., McNeil, B.J. (1988) Assessment of radiologic tests: control of bias and other design considerations. Radiology 167, 565-9.

Britten, S., Soensken, D.M., Bustillo, M., Coulham, C.B. (1994) Very early (24-56 days from last menstrual period) embryonic heart rate in normal pregnancies. Hum Reprod 9: 1771-4.

Brown, D.L., Emerson, D.S., Felker, R.E., Cartier, M.S., Smith, W.C. (1990) Diagnosis of early embryonic demise by endovaginal sonography. J Ultrasound Med 9: 631-6.

Coulham, C.B., Britten, S., Soensken, D.M. (1996) Very early (24-56 days from last menstrual period) ultrasonographic measurements in normal pregnancies. Hum Reprod 11: 2424-6.

Goldstein, S.R. (1992) Significance of cardiac activity on endovaginal ultrasound in very early embryos. Obstet Gynecol 80: 670-2.

Levi, C.S., Lyons, E.A., Lindsay, D.J. (1988) Early diagnosis of nonviable pregnancy with endovaginal US. Radiology 167, 383-5.

Levi, C.S., Lyons, E.A., Zheng, X.H., Lindsay, D.J., Holt S.C. (1990) Endovaginal US: Demonstration of cardiac activity in embryo’s of less than 5.0 mm in crown-rump length. Radiology 176: 71-4.

Steinkampf, M.P., Guzick, D.S., Hammond, K.R., Blackwell, R.E. (1997) Identification of early pregnancy landmarks by transvaginal sonography: analysis by logistic regression. Fertil Steril 68, 168-70.

Tongsong, T., Wanapirak, C., Srisomboon, J., Sirichotiyakul, S., Polsrisuthikul, T., Pngsatha, A. (1994) Transvaginal ultrasound in threatened abortions with empty gestational sacs. Int J Gynecol Obstet 46, 297-301.

Wilson, R.D., Kendrick, V., Wittmann, B.K., McGillivray, B. Spontaneous abortion and pregnancy outcome after normal first trimester ultrasound examination. Obstet Gynecol 67, 352-5.

Table I

* MSD = Mean gestational sac diameter; ^† CRL = Crown rump length

Table II
Results from first diagnostic ultrasound

Table III
Association between results of MSD- and CRL-measurement

Table IV
Results from last test sonography, i.e. the sonography that was performed before the reference sonography

Figure 1
ROC-curves for MSD and MSD adjusted for gestational age (MSD = mean gestational sac diameter).