Predicting Outcomes in Pregnancies of Unknown Location

Table 1. Published Studies on the Prediction of Ectopic Pregnancy in Women With a Pregnancy of Unknown Location
Year	Authors	Method	Sensitivity for detection of ectopic pregnancy (%)	Specificity for detection of ectopic pregnancy (%)	Area under the receiver operator characteristic curve	Comments	Ref.
1998	Mol etal.	Single progesterone level	17–100	28–100		•Meta-analysis summarizing evidence on the accuracy of a single progesterone measurement to diagnose ectopic pregnancy	^[10]
1998	Mol etal.	Discriminatory zone >2000 IU/l (TVS)			0.81	•A serum hCG of >2000 IU/l was found to indicate an ectopic pregnancy in women with no signs of an ectopic pregnancy on TVS •In women where TVS showed an ectopic mass or fluid in the Pouch of Douglas, a serum hCG >1500 IU/l indicated an ectopic pregnancy with almost certainty	^[36]
2004	Condous etal.	Logistic-regression model	91.7	84.2	0.885	•A logistic-regression model based on the hCG ratio (hCG 48h:hCG 0h) was developed and tested on 388 women with PULs	^[21]
2005	Condous etal.	Discriminatory zone >1000 IU/l (TVS) >1500 IU/l (TVS) >2000 IU/l (TVS)	21.7 15.2 10.9	87.3 93.4 95.2		•A prospective, observational study investigating 569 women with PUL •There were 46 ectopic pregnancies (8.7%) •Three different discriminatory zones were applied to the PUL population (1000, 1500 and 2000 IU/l) •Varying the discriminatory zone did not significantly improve the detection of ectopic pregnancy in the PUL population	^[13]
2005	Condous etal.	CA 125 levels			0.56	•Serum CA 125 levels, when incorporated into a logistic-regression model, were found to help distinguish failing PULs from IUPs, but were not able to detect those at risk of ectopic pregnancy	^[29]
2006	Seeber etal.	hCG curves	83	95.4		•The rate of change in serum hCG levels from two consecutive visits was determined and compared to a minimal rise of 35% in 2 days (99% CI for the rise in hCG in an IUP), or a minimal fall of 21–35% (90% CI for the fall in hCG in a spontaneous miscarriage)	^[16]
2007	Condous etal.	Logistic-regression model	80.0	88.6	0.90	•M4 is a multinomial logistic-regression model based on the log of the hCG average, the hCG ratio and its quadratic effect •When tested on a total of 376 PULs, it was found to outperform the previously published M1 model	^[22]
2007	Florio etal.	Serum activin A levels	100	99.6		•Activin A levels were found to be lowest in ectopic pregnancies, significantly lower than in IUPs or spontaneous miscarriages •When activin A levels were below a cutoff of 0.37 ng/ml, the positive predictive value for ectopic pregnancy was 97.4%, and was 0% for concentrations higher than 0.37 ng/ml	^[31]

Table 1. Published Studies on the Prediction of Ectopic Pregnancy in Women With a Pregnancy of Unknown Location
Year	Authors	Method	Sensitivity for detection of ectopic pregnancy (%)	Specificity for detection of ectopic pregnancy (%)	Area under the receiver operator characteristic curve	Comments	Ref.
1998	Mol etal.	Single progesterone level	17–100	28–100		•Meta-analysis summarizing evidence on the accuracy of a single progesterone measurement to diagnose ectopic pregnancy	^[10]
1998	Mol etal.	Discriminatory zone >2000 IU/l (TVS)			0.81	•A serum hCG of >2000 IU/l was found to indicate an ectopic pregnancy in women with no signs of an ectopic pregnancy on TVS •In women where TVS showed an ectopic mass or fluid in the Pouch of Douglas, a serum hCG >1500 IU/l indicated an ectopic pregnancy with almost certainty	^[36]
2004	Condous etal.	Logistic-regression model	91.7	84.2	0.885	•A logistic-regression model based on the hCG ratio (hCG 48h:hCG 0h) was developed and tested on 388 women with PULs	^[21]
2005	Condous etal.	Discriminatory zone >1000 IU/l (TVS) >1500 IU/l (TVS) >2000 IU/l (TVS)	21.7 15.2 10.9	87.3 93.4 95.2		•A prospective, observational study investigating 569 women with PUL •There were 46 ectopic pregnancies (8.7%) •Three different discriminatory zones were applied to the PUL population (1000, 1500 and 2000 IU/l) •Varying the discriminatory zone did not significantly improve the detection of ectopic pregnancy in the PUL population	^[13]
2005	Condous etal.	CA 125 levels			0.56	•Serum CA 125 levels, when incorporated into a logistic-regression model, were found to help distinguish failing PULs from IUPs, but were not able to detect those at risk of ectopic pregnancy	^[29]
2006	Seeber etal.	hCG curves	83	95.4		•The rate of change in serum hCG levels from two consecutive visits was determined and compared to a minimal rise of 35% in 2 days (99% CI for the rise in hCG in an IUP), or a minimal fall of 21–35% (90% CI for the fall in hCG in a spontaneous miscarriage)	^[16]
2007	Condous etal.	Logistic-regression model	80.0	88.6	0.90	•M4 is a multinomial logistic-regression model based on the log of the hCG average, the hCG ratio and its quadratic effect •When tested on a total of 376 PULs, it was found to outperform the previously published M1 model	^[22]
2007	Florio etal.	Serum activin A levels	100	99.6		•Activin A levels were found to be lowest in ectopic pregnancies, significantly lower than in IUPs or spontaneous miscarriages •When activin A levels were below a cutoff of 0.37 ng/ml, the positive predictive value for ectopic pregnancy was 97.4%, and was 0% for concentrations higher than 0.37 ng/ml	^[31]

Table 1. Published Studies on the Prediction of Ectopic Pregnancy in Women With a Pregnancy of Unknown Location
Year	Authors	Method	Sensitivity for detection of ectopic pregnancy (%)	Specificity for detection of ectopic pregnancy (%)	Area under the receiver operator characteristic curve	Comments	Ref.
1998	Mol etal.	Single progesterone level	17–100	28–100		•Meta-analysis summarizing evidence on the accuracy of a single progesterone measurement to diagnose ectopic pregnancy	^[10]
1998	Mol etal.	Discriminatory zone >2000 IU/l (TVS)			0.81	•A serum hCG of >2000 IU/l was found to indicate an ectopic pregnancy in women with no signs of an ectopic pregnancy on TVS •In women where TVS showed an ectopic mass or fluid in the Pouch of Douglas, a serum hCG >1500 IU/l indicated an ectopic pregnancy with almost certainty	^[36]
2004	Condous etal.	Logistic-regression model	91.7	84.2	0.885	•A logistic-regression model based on the hCG ratio (hCG 48h:hCG 0h) was developed and tested on 388 women with PULs	^[21]
2005	Condous etal.	Discriminatory zone >1000 IU/l (TVS) >1500 IU/l (TVS) >2000 IU/l (TVS)	21.7 15.2 10.9	87.3 93.4 95.2		•A prospective, observational study investigating 569 women with PUL •There were 46 ectopic pregnancies (8.7%) •Three different discriminatory zones were applied to the PUL population (1000, 1500 and 2000 IU/l) •Varying the discriminatory zone did not significantly improve the detection of ectopic pregnancy in the PUL population	^[13]
2005	Condous etal.	CA 125 levels			0.56	•Serum CA 125 levels, when incorporated into a logistic-regression model, were found to help distinguish failing PULs from IUPs, but were not able to detect those at risk of ectopic pregnancy	^[29]
2006	Seeber etal.	hCG curves	83	95.4		•The rate of change in serum hCG levels from two consecutive visits was determined and compared to a minimal rise of 35% in 2 days (99% CI for the rise in hCG in an IUP), or a minimal fall of 21–35% (90% CI for the fall in hCG in a spontaneous miscarriage)	^[16]
2007	Condous etal.	Logistic-regression model	80.0	88.6	0.90	•M4 is a multinomial logistic-regression model based on the log of the hCG average, the hCG ratio and its quadratic effect •When tested on a total of 376 PULs, it was found to outperform the previously published M1 model	^[22]
2007	Florio etal.	Serum activin A levels	100	99.6		•Activin A levels were found to be lowest in ectopic pregnancies, significantly lower than in IUPs or spontaneous miscarriages •When activin A levels were below a cutoff of 0.37 ng/ml, the positive predictive value for ectopic pregnancy was 97.4%, and was 0% for concentrations higher than 0.37 ng/ml	^[31]

Table 1. Published Studies on the Prediction of Ectopic Pregnancy in Women With a Pregnancy of Unknown Location
Year	Authors	Method	Sensitivity for detection of ectopic pregnancy (%)	Specificity for detection of ectopic pregnancy (%)	Area under the receiver operator characteristic curve	Comments	Ref.
1998	Mol etal.	Single progesterone level	17–100	28–100		•Meta-analysis summarizing evidence on the accuracy of a single progesterone measurement to diagnose ectopic pregnancy	^[10]
1998	Mol etal.	Discriminatory zone >2000 IU/l (TVS)			0.81	•A serum hCG of >2000 IU/l was found to indicate an ectopic pregnancy in women with no signs of an ectopic pregnancy on TVS •In women where TVS showed an ectopic mass or fluid in the Pouch of Douglas, a serum hCG >1500 IU/l indicated an ectopic pregnancy with almost certainty	^[36]
2004	Condous etal.	Logistic-regression model	91.7	84.2	0.885	•A logistic-regression model based on the hCG ratio (hCG 48h:hCG 0h) was developed and tested on 388 women with PULs	^[21]
2005	Condous etal.	Discriminatory zone >1000 IU/l (TVS) >1500 IU/l (TVS) >2000 IU/l (TVS)	21.7 15.2 10.9	87.3 93.4 95.2		•A prospective, observational study investigating 569 women with PUL •There were 46 ectopic pregnancies (8.7%) •Three different discriminatory zones were applied to the PUL population (1000, 1500 and 2000 IU/l) •Varying the discriminatory zone did not significantly improve the detection of ectopic pregnancy in the PUL population	^[13]
2005	Condous etal.	CA 125 levels			0.56	•Serum CA 125 levels, when incorporated into a logistic-regression model, were found to help distinguish failing PULs from IUPs, but were not able to detect those at risk of ectopic pregnancy	^[29]
2006	Seeber etal.	hCG curves	83	95.4		•The rate of change in serum hCG levels from two consecutive visits was determined and compared to a minimal rise of 35% in 2 days (99% CI for the rise in hCG in an IUP), or a minimal fall of 21–35% (90% CI for the fall in hCG in a spontaneous miscarriage)	^[16]
2007	Condous etal.	Logistic-regression model	80.0	88.6	0.90	•M4 is a multinomial logistic-regression model based on the log of the hCG average, the hCG ratio and its quadratic effect •When tested on a total of 376 PULs, it was found to outperform the previously published M1 model	^[22]
2007	Florio etal.	Serum activin A levels	100	99.6		•Activin A levels were found to be lowest in ectopic pregnancies, significantly lower than in IUPs or spontaneous miscarriages •When activin A levels were below a cutoff of 0.37 ng/ml, the positive predictive value for ectopic pregnancy was 97.4%, and was 0% for concentrations higher than 0.37 ng/ml	^[31]

Box 1. Summary of Consensus Statement Issued by the International Society of Uitrasound 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].

Sidebar: Executive Summary

Definition

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.

Management

Expectant management has been demonstrated to be safe for the majority of women classified with PULs.

Serum Progesterone Levels

Serum progesterone levels have been used to predict the outcome of PULs, but appear to be better at predicting pregnancy viability than pregnancy location.

Serum Human Chorionic Gonadotrophin Levels

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 48h expressed as the hCG ratio (hCG 48h:hCG 0h) is helpful in predicting the outcome of PULs.

Mathematical Models

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 48h.

Other Markers

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 andsimplicity.

Uterine Curettage

In most cases, uterine curettage should not play a role in the classification of PULs.

Future Perspective

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.

Predicting Outcomes in Pregnancies of Unknown Location

Diagnostic Laparoscopy

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