Acta Obstet Gynecol Scand 1990; 69: 505-509

DOUBLING TIME AND hCG SCORE FOR THE EARLY DIAGNOSIS OF ECTOPIC PREGNANCY IN ASYMPTOMATIC WOMEN Dick J. Tinga, J a n J . van Lier and Henk W.A. de Bruijn From the Department of Obstetrics and Gynaecology, State University Hospital, Groningen, The Netherlands

Abstract. In a group of 20 asymptomatic women at increased risk for ectopic pregnancy, serum analyses were conducted prospectively early in pregnancy (amenorrhea 1 4 5 days) at 24-day intervals, to examine the rate of increase in hCG values. The initial serum hCG level, which was determined at the time of the first transvaginal ultrasound examination, was below the discriminatory zone of 1000 IU/I (2nd International Standard). In 8 out of the 9 women who were ultimately diagnosed as having an ectopic pregnancy, the increase in hCG progressed only slowly, with a doubling time exceeding 2. 2 days. This slow hCG increase occurred in 2 out of the 11 women who were ultimately diagnosed a s having an intra-uterine pregnancy; both women subsequently had an early spontaneous abortion. When Lindblom's hCG score was applied retrospectively to distinguish between intra-uterine and ectopic pregnancies, the hCG increase in all the ectopic pregnancies was below 190 lull per day and in 10 of the 11 women with an intra-uterine pregnancy above 190 lull per day. A slower rate of increase was observed in only one woman with an intra-uterine pregnancy; she had a spontaneous abortion. The doubling time of hCG and the hCG score are useful diagnostic aids in cases where transvaginal ultrasound has not (yet) given a definite answer regarding the presence of an intra-uterine pregnancy. Key words: hCG, ectopic pregnancy, doubling time, hCG score, transvaginal ultrasound, discriminatory zone.

The direct ultrasonic demonstration of an early ectopic pregnancy is successful in 64-81 % of ectopic pregnancies if the transvaginal ultrasound technique is applied in women with symptoms (1,2). However, in asymptomatic women, it is still not clear how early in pregnancy and what proportion of women with an ectopic pregnancy can be diagnosed using transvaginal ultrasound. Generally, it is possible to diagnose an intra-uterine pregnancy from the sixth gestational week onwards with a great degree of certainty, by using ultrasound (3,4), which makes the presence of an ectopic pregnancy very unlikely, because a combination of intra-uterine and ectopic pregnancy is extremely rare. However, this combination occurs

hCG: human chorionic gonadotropin; 2nd IS: Second International Standard; DZ: discriminatory zone; DT: doubling time; ELISA: enzyme-linked immunosorbent assay; IU/L: International Units per litre; Mhz: megahertz; IUP: intra-uterine pregnancy; EP: ectopic pregnancy.

less seldom after in vitro fertilization and embryo transfer (5). It is wellknown that trophoblastic development is less than optimal in about 80% of ectopic pregnancies (6), which leads to a slower increase in the serum hCG level than is observed in cases with an intact IUP. We conducted a prospective investigation on the serum hCG values (in combination with ultrasound) within the first 10 days of being 'overdue' in initially asymptomatic women at increased risk for an ectopic pregnancy. This study was conducted to examine whether prospective serum hCG analyses can give an early indication of the subsequent course of pregnancy in women at increased risk for EP, in whom the transvaginal ultrasound examinations fail to demonstrate an IUP or EP in the fifth (or possibly sixth) week of pregnancy. The rate of increase in the hCG value can be expressed in terms of a doubling time (7) or hCG score (8). We compared the results and ultrasound images in the group of women who ultimately appeared to have an Acta Obstet Gynecol Scand 69 11990)

506

Dick J . Tingu et al.

Table I. Amenorrhea duration, serum hCG values, test interval, doubling times and hCG increases per day in subjects with IUP and EP /UP P.

A B C D E F

G H I J* K*

Av.

Am. 35 36 34 42 33 31 42 34 34 38 34 35.7

EP

hCGl

hCG2

TI

DT

480

1305 1970 906 900 3000 825 770 1335 2100 530 1100

2 4 2 2 4 3 3 2 3 2 2

1.4 1.8 2.1 1.6 2.2 1.6 1.4 1.4 1.6 3.3 2.3 2.6

413 472 380 870 230 175 505 565 350 600 458

hCG incr. 413 389 217 260 533 198 198 415 512 90 250

P.

Am.

hCGl

hCG2

TI

DT

hCG incr.

L M N 0 P Q R S T

36 36 34 40 36 36 37 42 39

500 350 357 965 170 585 198 357 330

865 835 600 1165 330 1285 615 540 665

2 3 2 2 3 4 3 2 3

2.5 2.4 5.3 6.4 3.1 3.5 1.8 3.3 3.0

183 162 121 100 53 175 139 92 112

37.3

423

2.7

P = subjects (A to T). = amenorrhea duration (in days) at time of first serum hCG test Am. = first serum hCG value (IUII, 2nd IS). hCG1 hCG2 = second serum hCG value (IUII, 2nd IS). TI = test interval (in days) between first and second test. = doubling time of hCG (in days). DT Av. = average (Am, hCG1, TI). hCG incr. = increase (in hCG IUIllday). *Women with IU pregnancy, who had a spontaneous abortion.

ectopic pregnancy, versus those in the group, of women who were ultimately diagnosed as having an intra-uterine pregnancy.

MATERIAL AND M E T HODS Twenty women at increased risk for ectopic pregnancy following tuba1 surgery (n=9), treatment for previous ectopic pregnancy (n=7), with a history of infection in the lower pelvis (n=2) or general infertility complaints (n=2) were informed of their increased risk and asked to report to the out-patient department if their menstrual period was 4 to 5 days overdue. In cases where the hCG (morning) urine test (threshold 50 IUA) was positive, blood was taken for quantitative hCG analysis. If there was no evidence of an intrauterine or ectopic pregnancy on clinical or ultrasound examination and the woman was clinically stable, she was asked to return to the Department 2 to 4 days later for repeat ultrasound and blood tests. The serum hCG analyses were performed using the f3subunit specific ELISA (Abbott Diagnostics, Chicago, USA), with the second International Standard (2nd IS) as reference (9, 10). All the asymptomatic, high-risk subjects were included in the study, provided they met the following criteria: a ) initial serum hCG value between 100 and loo0 IUA, b) test interval 2 to 4 days. These limitations were laid down for the following reasons: a ) with very low serum hCG levels (2.2 days was used which produced a sensitivity of 89% and a specificity of 82%. The positive predictive value of a DT of >2.2 days was 80% for the presence of an EP (Table 11). When Lindblom’s hCG score was applied (Fig. 2),

507

the best discrimination between IUP and EP was obtained by using the hCG increase at a cut-off level of 190 IU/I per day. A slower rate of increase was observed in only one woman with an IUP; she had a spontaneous abortion (Table I). Therefore, the rate of increase in hCG was of more predictive value and showed greater sensitivity and specificity than the DT (Table 11). After the second test in the EP group the hCG level continued to rise at a slow rate in 6 cases; in 2 cases the hCG level remained unchanged and in one case the hCG level dropped from 1165 to 265 IU/I and then remained steady. The initial ultrasound images in the EP group showed a small translucency (an apparent ‘fluid collection’ or ‘pseudo-sac’) in the uterus in one case and an ‘empty’ uterine cavity in all the others. The presence of an EP was suspected in only one case, in the form of a circumscribed light ultrasonic translucency outside the uterus, which was confirmed at repeat examinations and was later found to correspond to an ampullar pregnancy during laparotomy. The second series of ultrasound scans showed a second woman with an abnormality outside the uterus, which aroused suspicions of an EP. Five cases had a translucency in the uterine cavity which was similar in appearance to a ‘pseudo-sac’. The remaining three showed an ‘empty’ cavity. The initial ultrasound images of the IUP group suggested the presence of an IUP in 5 of the 11 cases; these 5 women had an hCG level of >400 IU/I. In the remaining 6 cases, the cavity appeared to be ‘empty’. The second ultrasound examination, after an average of 2.8 days, suggested an IUP in all 11 cases; the images of the 2 women who had a spontaneous abortion showed a small gestational sac of 2 and 3 mm, respectively. A diagnostic laparoscopy was performed in 9 cases and EP was confirmed an average of 4 days after the second serum hCG analysis. At this stage, 6 of the women had developed symptoms: slight abdominal discomfort ( n = 3 ) and slight bleeding ( n = 3 ) . None

Table II. Sensitivity, specificity and predictive valcIre of DT and hCG score for diagnosing EP

Sensitivity: Specificity: Predictive value (+)test: Predictive value (-)test:

(TPTTP + TN): (TNTTN + FP): (TPTTP + FP): (TPTTN + FN):

hCG increase

DT >2.2 days

c 190 IU/l/day

89% 82% 80% 90%

100% 91 % 90% 100% Acta Obster Gynecol Scand 69 (1990)

508

\

Dick J . Tinga er al.

0

500-

Fig. 2. Rate of hCG increase related to the initial serum hCG value in women with EP (0)and IUP (0). (*Women who aborted). Cut-off level: 190 IUIVday.

0

3

.Q

-' \

400-

0

O0

2 J

300-

0

s

*

0

9,

0

en

200-

-

0

8 100-

e

e1=. 0 *

I

I

I

200

1

a0

I

I

6h

of the women suffered a tuba1 rupture. Conservative surgical treatment consisted of salpingotomy in 8 cases and fimbrial expression in one case. In 7 of the 9 women, the serum hCG level at the time of the operation was >lo00 IU/I.

DISCUSSION By conducting serum analyses in the first 10 days that a woman was 'overdue' we were able to compare the diagnostic value of doubling times and hCG scores for screening women at risk for ectopic pregnancy. When serum hCG measurement is combined with ultrasound, which has been studied by several authors (12, 13), the use of the D Z is an important tool for diagnosis (1, 14, 15). When performing serial serum hCG analyses, the rate of increase in the serum hCG level can be expressed in terms of the doubling time (DT), or as an hCG score (7, 8). These tests can also be supplemented with ultrasound scanning (11, 16). The DT in an intact pregnancy varies between 1 . 4 and 2.2 days in the period of pregnancy, which corresponds to an amenorrhea duration of 23 to 35 days (10) following regular cycles of 28 days, and this is comparable to the DTs found in the intact IUP group, irrespective of amenorrhea duration - some patients in our study (IUP and EP group) had a longer menstrual cycle, as could be expected. This emphasizes the advantage of serial measurement of hCG. In the women without an intact IUP in our study group, it appeared that the doubling time was not a very reliable instrument to distinguish between IUP and EP. This has also been mentioned in the literaAcra Obsret Gynecol Srand 69 (1990)

I

1

eh

i

I

lh

"/I

ture (7). We had already suspected the presence of an IUP in the 2 women who had a spontaneous abortion, on the basis of the ultrasound images obtained at the second serum test. The application of Lindblom's hCG score produced higher sensitivity, specificity and positive and negative predictive values. The hCG levels to which we applied this score were much lower than those in the group studied by Lindblom et al. (8), (Fig. 2). Only one woman with an IUP, one of the 2 who had a spontaneous abortion, showed an absolute increase of less than 190 IU/l/day, whereas all the EPs showed and increase of el90 IU/Yday. We therefore conclude that the hCG score is a reliable method and is comparable to the use of DT. However, more research with a larger study population is necessary. Serial serum hCG analyses in addition to transvaginal ultrasound are indispensable for screening as well as for treatment purposes. In this way, unnecessary laparotomy can be avoided and replaced by one of the modern therapies which have a better chance of success in women with relatively low serum hCG values (17-19). REFERENCES Stiller RJ, Haynes de Regt R, Blair E. Transvaginal ultrasonography in patients at risk for ectopic pregnancy. Am J Obstet Gynecol 1989; 161: 930-3. Funk A , Fendel H. Verbesserte Diagnostik der Extrauteringraviditat durch die Endosonographie. Z Geburtsh u Perinat 1988; 192: 49-53. Bernaschek G, Rudelstorfer R, Csaicsich P. Vaginal sonography versus serum human chorionic gonadotropin in early detection of pregnancy. Am J Obstet Gynecol 1988; 158: 608-12. Fossum GT, Davajan V, Kletzky OA. Early detection

Doubling time and hCG score for the diagnosis of EP

5.

6.

7.

8.

Y.

10.

II.

12. 13.

of pregnancy with transvaginal ultrasound. Fertil Steril 1988; 49: 788-91. Dimitry ES, Subak-Sharpe R, Mills M, Margara R, Winston R. Nine cases of heterotopic pregnancies in 4 years of in vitro fertilization. Fertil Steril 1990; 53: 107- 10. Braunstein GD, Karow 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. Batzer FR, Schlaff S. Goldfarb AF. Corson SL. Serial [%subunit human chorionic gonadotropin doubling time as a prognosticator of pregnancy outcome in an infertile population. Fertil Steril 1981; 35: 307-12. Lindblom B. Hahlin M, Sjoblom P. Serial human chorionic gonadotropin determinations by fluoroimmunoassay for differentiation between intrauterine and ectopic gestation. Am J Obstet Gynecol 1989; 161: 397-400. Bangham DR, Storring PL. Standardisation of hCG, hCG subunits and pregnancy tests. Lancet 1982; i: 390. Pittaway DE. P-hCG dynamics in ectopic pregnancy. Clinical Obstet Gynecol 1987; 30: 129-35. Pittaway DE, Wentz AC, Maxson WS, Herbert C, Daniel1 J , Fleischer AC. The efficacy of early pregnancy monitoring with serial chorionic gonadotropin determinations and real-time sonography in an infertility population. Fertil Steril 1985; 44: 1904. Jouppila P. Tapanainen J . Huhtaniemi 1. Plasma hCG and ultrasound in suspected ectopic pregnancy. Eur J Ohstet Gynecol Reprod Biol 1980; 10: 3-12. Bryson SCP. 8 - Subunit of human chorionic gona-

14. 15.

16. 17. 18. 19.

SOY

dotropin, ultrasound, and ectopic pregnancy: A prospective study. Am J Obstet Gynecol 1983; 146: 163-5. Kadar N, DeVore G , Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981; 58: 156-61. Nyberg DA, Filly RA, Mahony BS, Monroe S, Laing FC, Jeffrey RB. Early gestation: correlation of HCG levels and sonographic identification. AJR 1985; 144: 9514. Dinsmoor M, Gibson M. Early recognition of ectopic pregnancy in an infertility population. Obstet Gynecol 1986; 68: 8 9 - 6 2 , Carp HJA, Oelsner G , Serr DM, Mashiach S. Fertility after nonsurgical treatment of ectopic pregnancy. J Reprod Med 1986; 31: 119-22. Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol 1986; 154: 1299-1306. Lindblom B, Kalfellt B, Hahlin M, Hamberger L. Local prostaglandin Ma injection for termination of ectopic pregnancy. Lancet 1987; i: 776-7.

Submitted for publication March IS, 1990 Accepted August 13, 1990 D.J. Tinga Dept of Obstetrics and Gynaecology State University Hospital Oostersingel 59 NL-9713 E Z Groningen The Netherlands

Acra Ohstet Gynecol Scand 69 (1990)