- Email: [email protected]
Prediction of early pregnancy outcomes
International Journal of Gynecology & Obstetrics 51 (1995) 33-38
Article
Prediction of early pregnancy outcomes Y.S. Lin*, C.H. Liu Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan, Taiwan Received 27 March 1995; revision received 12 June 1995; accepted 14 June 1995
AbStCNt Objective: A prospective study was performed on the conception hormones of early pregnancy in order to examine their sensitivity and predictability for early pregnancy loss. Merhod: The serum levels of progesterone, estradiol and human chorionic gonadotropin (hCG) were measured and analyzed at 5-8 weeks of gestation in pregnancies occurring both with and without ovarian stimulation. Results: If a level of C 10 ngknl of progesterone was chosen as the cut-off
value for the predictionof early pregnancyloss, the sensitivityand specificitywere 56%and 98%,respectively.The optimal cut-off value was chosen at ~0.5 multiplesof the median (MOM) and <0.4 MOM for estradiol and hCG, respectively. This gave a sensitivity of 80%for estradioland 85%for hCG, and a specificityof 93%for estradioland 81%for hCG at week8 of gestation.Conclusion: The combined determination of conception hormones is an effkacious method of monitoring early pregnancy and may be used for predicting outcome. Keywords: Early pregnancy; Progesterone; Estradiol; Human chorionic gonadotropin
1. ln-on
Early pregnancy failure is an important complication of human reproduction. Many studies have been carried out into methods of predicting early pregnancy loss, such as the estimation of serial human chorionic gonadotropin (hCG), the mean value of serum hCG levels [l-6], the doubling time of hCG production [7], the slope of hCG increment 181and the hCG scoring method [9,10]. * Corresponding author, Tel.: +886 6 2353535, Ext. 5221; Fax: +886 6 2766185.
However these reports have produced fluctuating sensitivities and specificities. Application of the multiples of the median (MOM) in assessing serum levels of conception hormones, which could decrease the influences of extreme values, was first described by Lower and Yovich 1111. In their report the cut-off levels of conception hormones obtained from the receiver-operator characteristic (RGC) curve may be useful in the prediction of early pregnancy loss. Inaccurate dating of pregnancies conceived spontaneously may adversely affect the reliability and usefulness
0020-7292!95i$O9.500 1995 International Federation of Gynecology and Obstetrics SSDI 0020-7292(95)02466-P
of hormone
estimations,
particular-
34
Y.S. Lin, C.H. Liu/ International JQUIW~
ly in ectopic pregnancy. However the last menstrual period and date of ovulation in patients conceiving after treatment at an infertility clinic are relatively accurate. Therefore prospective collection of serum samples and analysis of the results of pregnancies from an infertility clinic are more reliable and useful. A prospective study was performed on the conception hormones of early pregnancy at our infertility center in order to examine their sensitivity and predictability for early pregnancy loss. The serum levels of progesterone, estradiol and hCG were measured and analyzed at 5-8 weeks of gestation in pregnancies occurring both with and without ovarian stimulation. 2. Materials and methods 2. I. Subjects A prospective study was performed at the infertility center of the National Cheng Kung University Hospital between May 1990 and January 1992. One hundred fifty-six women who achieved singleton pregnancy were included. Conception was achieved either after spontaneous ovulation (57 women) or by ovulation induction (99 women) with clomifene citrate or human menopausal gonadotropin (hMG) combined with various assisted conception procedures. The serum data of the spontaneous ovulation group were used for the estimation of progesterone and estradiol. All the data of 157 women were used for hCG analysis. An hCG serum level of 225 mIU/ml (the WHO Third International Standard) on day 14 of the luteal phase or a positive result from a urine pregnancy test (Clearview [sensitivity for hCG: 50 mIU/ml]; Unipath, Bedford, UK) on the 1st day of the missed menstrual period was diagnosed as pregnancy.
of Gynecology
Obstetrics 51 (1995) 33-38
assay using commercially available kits (COAT-ACOUNT; Diagnostic Products Corporation, Los Angeles, CA, USA). Sonographic examination was performed simultaneously by transvaginal scanning. The gestational sac, fetal pole and fetal heart beat were examined and recorded. The early pregnancy failure group included spontaneous abortion, blighted ovum and ectopic pregnancy. Spontaneous abortion was defined as a pregnancy which miscarried after the detection of fetal heart activity. No evidence of a viable intrauterine fetus within the gestational sac at 7-8 weeks of gestation was regarded as a blighted ovum. Ectopic pregnancy was suspected when the serum hCG level was highly elevated but no evidence of intrauterine pregnancy was detected by ultrasound scanning at 7 weeks of gestation, in which case laparoscopic examination was performed for confirmation of the diagnosis. 2.3. Statistics For the statistical analysis the serum levels of progesterone were expressed in nanograms per milliliter, and the hormone concentrations of estradiol and hCG were expressed as MOM values. Student’s t-test was used to compare the hormones between subjects with (99 women) and without (57 women) ovarian stimulation. Low serum levels of progesterone, estradiol or hCG were proposed as
I T
2.2. Methodr In patients who were diagnosed as pregnant, venous blood was obtained from the antecubital vein for the measurement of progesterone, estradiol and hCG at 5,6, 7 and 8 weeks of menstrual gestational age. The blood samples were sent to a central laboratory for examination of the serum level of conception hormones by radioimmuno-
&
0.2
Y 0.1 01
I
0
Q
0.1
0.2
0.3
0.4
0.5
FALSE POSITIVE RATE (l-!SPECIFICITY)
Fig. 1. ROC curve of progesterone in the fetal loss prediction test.
Y.S. Lin. C.H. Liu/ International Journal of
a positive test for early pregnancy failure. The cutoff values were chosen from the RGC curve analysis as shown in Fig. 1.
Gynecology &
Obstetrics 51 (1995) 33-38
Table 2 The median and MOM serum values of estradiol and hCG Week of gestation
3. Results
5
One hundred fifty-six patients who achieved singleton pregnancy were included in the study. Ninety-nine of the 156 pregnancy cycles occurred after ovulation induction using either clomifene citrate or hMG. A further 57 patients achieved pregnancy in spontaneous ovulatory cycles. The outcomes of pregnancy were categorized for the analysis into the ongoing pregnancy and the fetal loss group. The fetal loss group included spontaneous abortion, ectopic pregnancy and blighted ovum. The data obtained between 5 and 8 gestational weeks for each category are shown in Table 1. The median and MOM serum values of estradiol and hCG are listed in Table 2. The serum data of progesterone of the unstimulated conception cycles from 5 to 8 weeks of gestation were cumulated for the statistical analysis. The highest test efficiency for the prediction of pathological pregnancy obtained from
35
Bstradiol @g/ml)’ Median 0.5 MOM hCG (mIU/ml)b Median 0.4 MOM
7
6
299 150
301 151
715 358
776 388
2666 1066
12 351 4940
20 339 8136
32 849 13 140
%pontaneous ovulatory cycles. bBoth spontaneous and stimulated ovulatory cycles.
ROC curve analysis was noted (Fig. 1); if a progesterone level of < 10 ng/ml was chosen as the cut-off value (Table 3, Fig. 2), the sensitivity and specificity of this test were 56O/oand 98%, respectively. The serum levels of estradiol of the ovarian stimulated cycles were significantly higher than those of the unstimulated cycles for each respective gestational week (P c 0.05). Therefore the data of estradiol in the stimulated group were not used in the analysis. The optimal cut-off value for the pre-
Table I Classifcation of patients at weeks 5-8 of gestational age according to each category of pregnancy outcome Gestational age (weeks)
Progesteronea 5 6 7 8 Estradiola 5 6 7 8 hCGb 5 6 7 8
Ongoing PmgnancY
Pregnancy failure Spontaneous abortion
1
&topic pregnancy
Blighted ovum
Total
4 6 4 3
2 1 3 2
7 II 7 7
2
13 17 13 I5
4 0 2
11 16 13 15
0 4 0 2
4 6 2
I
3 2
6 11 5 5
41 49 42 31
8 13 5 7
6 10 5 3
3 5 6 3
17 28 16 13
%pontaneous ovulatory cycles. bBoth spontaneous and stimulated ovulatory cycles.
8
I
Y.S. Lin, CM. Liu /international Journal of Gynecology & Obstetrics 51 (1995) 33-38
36
Table 3 Sensitivity, speciScity and positive predictive value (PPV) of progesterone, estradiol and hCG in the detection of early pregnancy failure at 5-8 weeks of gestation Sensitivity (W
Gestational age (weeks)
Specificity (W
Progesterone < 10 n&ml* 5-8 56 Estradiol co.5 MOM* 5 50 6 46 7 80 8 80 hCG co.4 MoMb 5 59 6 15 I 81 8 85
100 -
0
- 0 :
,D z I-.’
ONQOINQ PREQNANCY PETAL LOSS 0
i A D
PPV (W
0
0.6 MOM
00 [D
i
’ :
pa.. 0
ti
00
95
98
:
0
0.1 E
00
0
100 100 85 93
100 100 61 80
66 14 14 81
42 62 54 65
0
0.01’
6
6
7
QESTATIONAL
S
WEEKS
Fig. 3. Serum estradiol levels (MOM) in patients with ongoing pregnancy and fetal loss at 5-8 weeks of gestation. The dotted line (0.5 MOM) refers to the cut-off level derived from the RGC curve (patients without ovarian stimulation).
*Spontaneous ovulatory cycles. bJ30th spontaneous and stimulated ovulatory cycles.
diction of early pregnancy loss was chosen at < 0.5 MOM for estradiol (Table 3, Fig. 3), which gave a sensitivity of 80% and a specificity of 93% at 8 gestational weeks. However no significant difference was observed between the serum levels of hCG in cycles with or without ovarian stimulated cycles. We pooled all the hCG data for the analysis. A cut-off level of co.4 MOM for hCG gave a sensi-
tivity and specificity at 7-8 weeks of gestation of 81-85% and 74-81%, respectively (Table 3, Fig. 4). From the analysis of the ROC curves for estradiol and hCG, the test efficiency for the prediction of early pregnancy failure increased with gestational age. 4. Discussion The estimation of gestational age in cctopic pregnancy was relatively uncertain in predicting
1000 !i : E
f :, P E
- 0
ONQOINQ PREQNANCV
- 0
FETAL L@S
0 cz
,DD z ‘.‘.-- 10 “~hnl
,. ___....__........................ * ~ 0
0
0
0
ONGOING PREQNANCY FETAL LOSS 00
0.4 MOM 0.1’ 6
7
6 GESTATIONAL
8
WEEKS
Fig. 2. Serum progesterone levels in patients with ongoing pregnancy and fetal loss at 5-8 weeks of gestation. The dotted line (10 ng/ml) refers to the cut-off level derived from the ROC curve (patients without ovarian stimulation).
V.“”
I
5
7
6 GESTATIONAL
8
WEEKS
Fig. 4. Serum hCG levels (MOM) in patients with ongoing pregnancy and fetal loss at 5-8 weeks of gestation. The dotted line (0.4 MOM) refers to the cut-off level derived from the RGC curve (patients with and without ovarian stimulation).
Y.S. Lin. C.H. Liu/International
Journal of Gynecology di Obstetrics 51 (1995) 33-38
early pregnancy failure. All patients included in this study had conceived under close monitoring of ovulation. Therefore the gestational age of each category of pregnancy failure was certain, and the collection of serum according to gestational age was more reliable in this study. Estimation of serum values of estradiol and hCG was expressed as MOM in order to decrease the influence of the extreme values at each gestational age. The cut-off values were chosen after analyzing the ROC curves [12] to select the optimal cut-off points to improve the sensitivity and specificity of the test. As noted in previous reports [2,3,13,14], somewhat unlike hCG titers, the serum progesterone level was independent of gestational age at 5-8 weeks of gestation. In our study the serum data of progesterone from 5 to 8 weeks of gestation were pooled for the statistical analysis. Duriug this period, 98% of the ongoing pregnancies had serum progesterone values r 10 ng/ml (specificity), whereas 56% of fetal losses had serum progesterone values < 10 @ml (sensitivity). In other words, 95% of the cases with progesterone levels < 10 @ml resulted in early pregnancy failure (positive predictive value). Our results are similar to those of previous reports [ 10,13,15] in that the specificity of the diagnostic test using progesterone cut-off points of 10 ng/ml and 9.4 ng/ml was 98% and 95-lOO%, respectively. The high specificities of these tests implies that a single progesterone assay is a suitable screening tool for early pregnancy failure. The test efficiencies of the ROC curves for estradiol and hCG increased with gestational age. Discrimination between ongoing pregnancy and early pregnancy losses became apparent at 7-8 weeks of gestation. At week 8 of gestation, 93% of ongoing pregnancies had estradiol levels ~0.5 MOM, and 81% of ongoing pregnancies had hCG levels 20.4 MOM. The sensitivity of estradiol and hCG at week 8 of gestation was better than that for progesterone (80-85% vs. 56%). This implies that low serum levels of estradiol and hCG were more closely associated with pregnancy loss than low progesterone levels at 7-8 weeks of gestation. With an accurate gestational age, a single estimation of conception hormones is possible for the diagnosis of early pregnancy failure 2 days sooner
31
than repeated hCG determinations. As Buyalos et al. [la] reported, the combination of measurement of these three hormones enhanced the speciIicity and predictive value in the prediction of pathologic pregnancy. Therefore we conclude that the combined determination of these conception hormones provides an efficacious method of monitoring high-risk pregnancies at an earlier stage, and may reduce the emergent presentation of ectopic pregnancy. In summary the data presented in this study should be useful in the prediction of early pregnancy failure. They could be beneficial in making an early diagnosis of abnormal pregnancy, thus avoiding the emergent presentation of an ectopic pregnancy and enabling early action to be taken for blighted ovum. Acknowledgmenta The authors are grateful to Miss S.T. Ho for her assistance with the serum collection and data management. We also thank the technicians of the Central Laboratory of National Cheng Kung University Hospital for the hormone assays. References 111Braunstein GD, Rarow WG, Gentry WC, Rasor J, Wade ME. First-trimester chorionic gonadotropin measurements as an aid in the diagnosis of early pregnancy disorders. Am J Obstet Gynecol 1978; 131: 25-32. 121Jovanovic L, Dawood MY, Lam&man R, Saxena BB. Hormonal profde as a prognostic index of early threatened abortion. Am J Obstet Gynecol 1978; 130: 274-278. 131 Aspillaga MO, Whittaker PG, Gmy CE, Lind T. Endocrinologic events in early pregnancy failure. Am J Obstet Gynecol 1983; 147: 903-908. [41 Contino E, Demir RH, Friberg J, Gleicher N. The predictive value of hCG &subunit levels in pregnancies achieved by in vitro fertilization and embryo transfer: an international collaborative study. Fertil Steril 1986; 45: 526-531. [51 Whittaker PG, Stewart MO, Taylor A, Lind T. Some endocrinological events associated with early pregnancy failure. Br J Obstet Gynaecol 1989; 96: 1207-1214. WI Yamashita T, MacLachlan V, Okamoto S, Healy DL, Thomas A. Predicting pregnancy outcome after in vitro fertilization and embryo transfer using estradiol, progesterone, and human chorionic gonadotropin &subunit. Fertil Steril 1989; 51: 304-309.
38
Y.S. Lin, C.H. Liu/ Inlewzational Journal of Gynecology & Obstetrics 51 (1995) 33-38
[7] Pittaway DE, Wentz AC, Maxson WS, Herbert
C, Daniell J, Fe&her AC. The efBcacy of early pregnancy monitoring with serial chorionic gonadotropin determinations and real-time sonography in an infertility pop ulation. Fertil Steril 1985; 44: 190-194. [8] Romero R, Kadar N, Cope1 JA, Jenty P, DeChemey AH, Hobbins JC. The value of serial human chorionic gonadotropin testing as a diagnostic tool in ectopic pregnancy. Am J Obstet Gynecol 1986; 155: 392-394. 191 Lindblom B, Hahlin M, Sjolom P. Serial human chorionic gonadotropin determinations by fluoroimmunoassay for differentiation between intrauterine and ectopic gestation. Am J Obstet Gynecol 1989; 161: 397-400. [lo] Hahlin M, Sjolom P, Lindblom B. Combined use ofprogesterone and human chorionic gonadotropin detenninations for differential diagnosis of very early pregnancy. Fertil Steril 1991; 55: 492-496. [II] Lower AM, Yovich JL. The value of serum levels of oestradiol, progsterone and &human chorionic gonadotrophin in the prediction of early pregnancy loss. Hum Reprod 1992; 7: 711-717.
[12] Richardson DK, Schwartz JS, Weinhaum PJ, Gabbe SG. Diagnostic tests in obstetrics: a method for improved evaluation. Am J Obstet Gynecol 1985; 152: 613-618. [13] Stovall TG, Ling FW, Anderson RN, Buster JE. Improved sensitivity and specificity of a single measurement of serum progesterone over serial quantitative betahuman chorionic gonadotropin in screening for ectopic pregnancy. Hum Reprod 1992; 7: 723-725. 1141 Cowan BD. Vandermolen DT, Long CA, Whitworth NS. Receiver-operator characteristic, efliciency analysis, and predictive value of serum progesterone concentration as a test for abnormal gestations. Am J Obstet Gynecol 1992; 166: 1729-1737. [15] Hahlin M, Wallin A, Sjolom P, Lindblom B. Single progesterone assay for early recognition of abnormal pregnancy. Hum Reprod 1990, 5: 622-626. [16] Buyalos RP, Glassman LM, Riflta SM, Falk RJ, Macarthy PO, Tyson VJ et al. Serum &human chorionic gonadotropin, estradiol and progesterone as early predictors of pathologic pregnancy. J Reprod Med 1992; 37: 261-266.
Article
Prediction of early pregnancy outcomes Y.S. Lin*, C.H. Liu Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan, Taiwan Received 27 March 1995; revision received 12 June 1995; accepted 14 June 1995
AbStCNt Objective: A prospective study was performed on the conception hormones of early pregnancy in order to examine their sensitivity and predictability for early pregnancy loss. Merhod: The serum levels of progesterone, estradiol and human chorionic gonadotropin (hCG) were measured and analyzed at 5-8 weeks of gestation in pregnancies occurring both with and without ovarian stimulation. Results: If a level of C 10 ngknl of progesterone was chosen as the cut-off
value for the predictionof early pregnancyloss, the sensitivityand specificitywere 56%and 98%,respectively.The optimal cut-off value was chosen at ~0.5 multiplesof the median (MOM) and <0.4 MOM for estradiol and hCG, respectively. This gave a sensitivity of 80%for estradioland 85%for hCG, and a specificityof 93%for estradioland 81%for hCG at week8 of gestation.Conclusion: The combined determination of conception hormones is an effkacious method of monitoring early pregnancy and may be used for predicting outcome. Keywords: Early pregnancy; Progesterone; Estradiol; Human chorionic gonadotropin
1. ln-on
Early pregnancy failure is an important complication of human reproduction. Many studies have been carried out into methods of predicting early pregnancy loss, such as the estimation of serial human chorionic gonadotropin (hCG), the mean value of serum hCG levels [l-6], the doubling time of hCG production [7], the slope of hCG increment 181and the hCG scoring method [9,10]. * Corresponding author, Tel.: +886 6 2353535, Ext. 5221; Fax: +886 6 2766185.
However these reports have produced fluctuating sensitivities and specificities. Application of the multiples of the median (MOM) in assessing serum levels of conception hormones, which could decrease the influences of extreme values, was first described by Lower and Yovich 1111. In their report the cut-off levels of conception hormones obtained from the receiver-operator characteristic (RGC) curve may be useful in the prediction of early pregnancy loss. Inaccurate dating of pregnancies conceived spontaneously may adversely affect the reliability and usefulness
0020-7292!95i$O9.500 1995 International Federation of Gynecology and Obstetrics SSDI 0020-7292(95)02466-P
of hormone
estimations,
particular-
34
Y.S. Lin, C.H. Liu/ International JQUIW~
ly in ectopic pregnancy. However the last menstrual period and date of ovulation in patients conceiving after treatment at an infertility clinic are relatively accurate. Therefore prospective collection of serum samples and analysis of the results of pregnancies from an infertility clinic are more reliable and useful. A prospective study was performed on the conception hormones of early pregnancy at our infertility center in order to examine their sensitivity and predictability for early pregnancy loss. The serum levels of progesterone, estradiol and hCG were measured and analyzed at 5-8 weeks of gestation in pregnancies occurring both with and without ovarian stimulation. 2. Materials and methods 2. I. Subjects A prospective study was performed at the infertility center of the National Cheng Kung University Hospital between May 1990 and January 1992. One hundred fifty-six women who achieved singleton pregnancy were included. Conception was achieved either after spontaneous ovulation (57 women) or by ovulation induction (99 women) with clomifene citrate or human menopausal gonadotropin (hMG) combined with various assisted conception procedures. The serum data of the spontaneous ovulation group were used for the estimation of progesterone and estradiol. All the data of 157 women were used for hCG analysis. An hCG serum level of 225 mIU/ml (the WHO Third International Standard) on day 14 of the luteal phase or a positive result from a urine pregnancy test (Clearview [sensitivity for hCG: 50 mIU/ml]; Unipath, Bedford, UK) on the 1st day of the missed menstrual period was diagnosed as pregnancy.
of Gynecology
Obstetrics 51 (1995) 33-38
assay using commercially available kits (COAT-ACOUNT; Diagnostic Products Corporation, Los Angeles, CA, USA). Sonographic examination was performed simultaneously by transvaginal scanning. The gestational sac, fetal pole and fetal heart beat were examined and recorded. The early pregnancy failure group included spontaneous abortion, blighted ovum and ectopic pregnancy. Spontaneous abortion was defined as a pregnancy which miscarried after the detection of fetal heart activity. No evidence of a viable intrauterine fetus within the gestational sac at 7-8 weeks of gestation was regarded as a blighted ovum. Ectopic pregnancy was suspected when the serum hCG level was highly elevated but no evidence of intrauterine pregnancy was detected by ultrasound scanning at 7 weeks of gestation, in which case laparoscopic examination was performed for confirmation of the diagnosis. 2.3. Statistics For the statistical analysis the serum levels of progesterone were expressed in nanograms per milliliter, and the hormone concentrations of estradiol and hCG were expressed as MOM values. Student’s t-test was used to compare the hormones between subjects with (99 women) and without (57 women) ovarian stimulation. Low serum levels of progesterone, estradiol or hCG were proposed as
I T
2.2. Methodr In patients who were diagnosed as pregnant, venous blood was obtained from the antecubital vein for the measurement of progesterone, estradiol and hCG at 5,6, 7 and 8 weeks of menstrual gestational age. The blood samples were sent to a central laboratory for examination of the serum level of conception hormones by radioimmuno-
&
0.2
Y 0.1 01
I
0
Q
0.1
0.2
0.3
0.4
0.5
FALSE POSITIVE RATE (l-!SPECIFICITY)
Fig. 1. ROC curve of progesterone in the fetal loss prediction test.
Y.S. Lin. C.H. Liu/ International Journal of
a positive test for early pregnancy failure. The cutoff values were chosen from the RGC curve analysis as shown in Fig. 1.
Gynecology &
Obstetrics 51 (1995) 33-38
Table 2 The median and MOM serum values of estradiol and hCG Week of gestation
3. Results
5
One hundred fifty-six patients who achieved singleton pregnancy were included in the study. Ninety-nine of the 156 pregnancy cycles occurred after ovulation induction using either clomifene citrate or hMG. A further 57 patients achieved pregnancy in spontaneous ovulatory cycles. The outcomes of pregnancy were categorized for the analysis into the ongoing pregnancy and the fetal loss group. The fetal loss group included spontaneous abortion, ectopic pregnancy and blighted ovum. The data obtained between 5 and 8 gestational weeks for each category are shown in Table 1. The median and MOM serum values of estradiol and hCG are listed in Table 2. The serum data of progesterone of the unstimulated conception cycles from 5 to 8 weeks of gestation were cumulated for the statistical analysis. The highest test efficiency for the prediction of pathological pregnancy obtained from
35
Bstradiol @g/ml)’ Median 0.5 MOM hCG (mIU/ml)b Median 0.4 MOM
7
6
299 150
301 151
715 358
776 388
2666 1066
12 351 4940
20 339 8136
32 849 13 140
%pontaneous ovulatory cycles. bBoth spontaneous and stimulated ovulatory cycles.
ROC curve analysis was noted (Fig. 1); if a progesterone level of < 10 ng/ml was chosen as the cut-off value (Table 3, Fig. 2), the sensitivity and specificity of this test were 56O/oand 98%, respectively. The serum levels of estradiol of the ovarian stimulated cycles were significantly higher than those of the unstimulated cycles for each respective gestational week (P c 0.05). Therefore the data of estradiol in the stimulated group were not used in the analysis. The optimal cut-off value for the pre-
Table I Classifcation of patients at weeks 5-8 of gestational age according to each category of pregnancy outcome Gestational age (weeks)
Progesteronea 5 6 7 8 Estradiola 5 6 7 8 hCGb 5 6 7 8
Ongoing PmgnancY
Pregnancy failure Spontaneous abortion
1
&topic pregnancy
Blighted ovum
Total
4 6 4 3
2 1 3 2
7 II 7 7
2
13 17 13 I5
4 0 2
11 16 13 15
0 4 0 2
4 6 2
I
3 2
6 11 5 5
41 49 42 31
8 13 5 7
6 10 5 3
3 5 6 3
17 28 16 13
%pontaneous ovulatory cycles. bBoth spontaneous and stimulated ovulatory cycles.
8
I
Y.S. Lin, CM. Liu /international Journal of Gynecology & Obstetrics 51 (1995) 33-38
36
Table 3 Sensitivity, speciScity and positive predictive value (PPV) of progesterone, estradiol and hCG in the detection of early pregnancy failure at 5-8 weeks of gestation Sensitivity (W
Gestational age (weeks)
Specificity (W
Progesterone < 10 n&ml* 5-8 56 Estradiol co.5 MOM* 5 50 6 46 7 80 8 80 hCG co.4 MoMb 5 59 6 15 I 81 8 85
100 -
0
- 0 :
,D z I-.’
ONQOINQ PREQNANCY PETAL LOSS 0
i A D
PPV (W
0
0.6 MOM
00 [D
i
’ :
pa.. 0
ti
00
95
98
:
0
0.1 E
00
0
100 100 85 93
100 100 61 80
66 14 14 81
42 62 54 65
0
0.01’
6
6
7
QESTATIONAL
S
WEEKS
Fig. 3. Serum estradiol levels (MOM) in patients with ongoing pregnancy and fetal loss at 5-8 weeks of gestation. The dotted line (0.5 MOM) refers to the cut-off level derived from the RGC curve (patients without ovarian stimulation).
*Spontaneous ovulatory cycles. bJ30th spontaneous and stimulated ovulatory cycles.
diction of early pregnancy loss was chosen at < 0.5 MOM for estradiol (Table 3, Fig. 3), which gave a sensitivity of 80% and a specificity of 93% at 8 gestational weeks. However no significant difference was observed between the serum levels of hCG in cycles with or without ovarian stimulated cycles. We pooled all the hCG data for the analysis. A cut-off level of co.4 MOM for hCG gave a sensi-
tivity and specificity at 7-8 weeks of gestation of 81-85% and 74-81%, respectively (Table 3, Fig. 4). From the analysis of the ROC curves for estradiol and hCG, the test efficiency for the prediction of early pregnancy failure increased with gestational age. 4. Discussion The estimation of gestational age in cctopic pregnancy was relatively uncertain in predicting
1000 !i : E
f :, P E
- 0
ONQOINQ PREQNANCV
- 0
FETAL L@S
0 cz
,DD z ‘.‘.-- 10 “~hnl
,. ___....__........................ * ~ 0
0
0
0
ONGOING PREQNANCY FETAL LOSS 00
0.4 MOM 0.1’ 6
7
6 GESTATIONAL
8
WEEKS
Fig. 2. Serum progesterone levels in patients with ongoing pregnancy and fetal loss at 5-8 weeks of gestation. The dotted line (10 ng/ml) refers to the cut-off level derived from the ROC curve (patients without ovarian stimulation).
V.“”
I
5
7
6 GESTATIONAL
8
WEEKS
Fig. 4. Serum hCG levels (MOM) in patients with ongoing pregnancy and fetal loss at 5-8 weeks of gestation. The dotted line (0.4 MOM) refers to the cut-off level derived from the RGC curve (patients with and without ovarian stimulation).
Y.S. Lin. C.H. Liu/International
Journal of Gynecology di Obstetrics 51 (1995) 33-38
early pregnancy failure. All patients included in this study had conceived under close monitoring of ovulation. Therefore the gestational age of each category of pregnancy failure was certain, and the collection of serum according to gestational age was more reliable in this study. Estimation of serum values of estradiol and hCG was expressed as MOM in order to decrease the influence of the extreme values at each gestational age. The cut-off values were chosen after analyzing the ROC curves [12] to select the optimal cut-off points to improve the sensitivity and specificity of the test. As noted in previous reports [2,3,13,14], somewhat unlike hCG titers, the serum progesterone level was independent of gestational age at 5-8 weeks of gestation. In our study the serum data of progesterone from 5 to 8 weeks of gestation were pooled for the statistical analysis. Duriug this period, 98% of the ongoing pregnancies had serum progesterone values r 10 ng/ml (specificity), whereas 56% of fetal losses had serum progesterone values < 10 @ml (sensitivity). In other words, 95% of the cases with progesterone levels < 10 @ml resulted in early pregnancy failure (positive predictive value). Our results are similar to those of previous reports [ 10,13,15] in that the specificity of the diagnostic test using progesterone cut-off points of 10 ng/ml and 9.4 ng/ml was 98% and 95-lOO%, respectively. The high specificities of these tests implies that a single progesterone assay is a suitable screening tool for early pregnancy failure. The test efficiencies of the ROC curves for estradiol and hCG increased with gestational age. Discrimination between ongoing pregnancy and early pregnancy losses became apparent at 7-8 weeks of gestation. At week 8 of gestation, 93% of ongoing pregnancies had estradiol levels ~0.5 MOM, and 81% of ongoing pregnancies had hCG levels 20.4 MOM. The sensitivity of estradiol and hCG at week 8 of gestation was better than that for progesterone (80-85% vs. 56%). This implies that low serum levels of estradiol and hCG were more closely associated with pregnancy loss than low progesterone levels at 7-8 weeks of gestation. With an accurate gestational age, a single estimation of conception hormones is possible for the diagnosis of early pregnancy failure 2 days sooner
31
than repeated hCG determinations. As Buyalos et al. [la] reported, the combination of measurement of these three hormones enhanced the speciIicity and predictive value in the prediction of pathologic pregnancy. Therefore we conclude that the combined determination of these conception hormones provides an efficacious method of monitoring high-risk pregnancies at an earlier stage, and may reduce the emergent presentation of ectopic pregnancy. In summary the data presented in this study should be useful in the prediction of early pregnancy failure. They could be beneficial in making an early diagnosis of abnormal pregnancy, thus avoiding the emergent presentation of an ectopic pregnancy and enabling early action to be taken for blighted ovum. Acknowledgmenta The authors are grateful to Miss S.T. Ho for her assistance with the serum collection and data management. We also thank the technicians of the Central Laboratory of National Cheng Kung University Hospital for the hormone assays. References 111Braunstein GD, Rarow WG, Gentry WC, Rasor J, Wade ME. First-trimester chorionic gonadotropin measurements as an aid in the diagnosis of early pregnancy disorders. Am J Obstet Gynecol 1978; 131: 25-32. 121Jovanovic L, Dawood MY, Lam&man R, Saxena BB. Hormonal profde as a prognostic index of early threatened abortion. Am J Obstet Gynecol 1978; 130: 274-278. 131 Aspillaga MO, Whittaker PG, Gmy CE, Lind T. Endocrinologic events in early pregnancy failure. Am J Obstet Gynecol 1983; 147: 903-908. [41 Contino E, Demir RH, Friberg J, Gleicher N. The predictive value of hCG &subunit levels in pregnancies achieved by in vitro fertilization and embryo transfer: an international collaborative study. Fertil Steril 1986; 45: 526-531. [51 Whittaker PG, Stewart MO, Taylor A, Lind T. Some endocrinological events associated with early pregnancy failure. Br J Obstet Gynaecol 1989; 96: 1207-1214. WI Yamashita T, MacLachlan V, Okamoto S, Healy DL, Thomas A. Predicting pregnancy outcome after in vitro fertilization and embryo transfer using estradiol, progesterone, and human chorionic gonadotropin &subunit. Fertil Steril 1989; 51: 304-309.
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[7] Pittaway DE, Wentz AC, Maxson WS, Herbert
C, Daniell J, Fe&her AC. The efBcacy of early pregnancy monitoring with serial chorionic gonadotropin determinations and real-time sonography in an infertility pop ulation. Fertil Steril 1985; 44: 190-194. [8] Romero R, Kadar N, Cope1 JA, Jenty P, DeChemey AH, Hobbins JC. The value of serial human chorionic gonadotropin testing as a diagnostic tool in ectopic pregnancy. Am J Obstet Gynecol 1986; 155: 392-394. 191 Lindblom B, Hahlin M, Sjolom P. Serial human chorionic gonadotropin determinations by fluoroimmunoassay for differentiation between intrauterine and ectopic gestation. Am J Obstet Gynecol 1989; 161: 397-400. [lo] Hahlin M, Sjolom P, Lindblom B. Combined use ofprogesterone and human chorionic gonadotropin detenninations for differential diagnosis of very early pregnancy. Fertil Steril 1991; 55: 492-496. [II] Lower AM, Yovich JL. The value of serum levels of oestradiol, progsterone and &human chorionic gonadotrophin in the prediction of early pregnancy loss. Hum Reprod 1992; 7: 711-717.
[12] Richardson DK, Schwartz JS, Weinhaum PJ, Gabbe SG. Diagnostic tests in obstetrics: a method for improved evaluation. Am J Obstet Gynecol 1985; 152: 613-618. [13] Stovall TG, Ling FW, Anderson RN, Buster JE. Improved sensitivity and specificity of a single measurement of serum progesterone over serial quantitative betahuman chorionic gonadotropin in screening for ectopic pregnancy. Hum Reprod 1992; 7: 723-725. 1141 Cowan BD. Vandermolen DT, Long CA, Whitworth NS. Receiver-operator characteristic, efliciency analysis, and predictive value of serum progesterone concentration as a test for abnormal gestations. Am J Obstet Gynecol 1992; 166: 1729-1737. [15] Hahlin M, Wallin A, Sjolom P, Lindblom B. Single progesterone assay for early recognition of abnormal pregnancy. Hum Reprod 1990, 5: 622-626. [16] Buyalos RP, Glassman LM, Riflta SM, Falk RJ, Macarthy PO, Tyson VJ et al. Serum &human chorionic gonadotropin, estradiol and progesterone as early predictors of pathologic pregnancy. J Reprod Med 1992; 37: 261-266.