The Value of Urinary Pregnanediol Estimation for Monitoring Early Pregnancies

FERTILITY AND STERILITY Copyright © 1978 The American Fertility Society

Vol. 29, No.2, February 1978 Printed in UB.A.

THE VALUE OF URINARY PREGNANEDIOL ESTIMATION FOR MONITORING EARLY PREGNANCIES

DINU BERNSTEIN, M.D. H. BENJAMIN FRISHMAN, M.D. SAMUEL LEVIN, M.D.* SARAH SCHWARTZ, M.Sc.

Department of Obstetrics and Gynecology, Donolo-Zahalon Government Hospital, and Tel Aviv University-Sackler Medical School, Tel Aviv-Jaffa, Israel

Urine samples from 76 pregnant women were tested for pregnanediol content during the first 6 weeks of pregnancy. Pregnanediol was measured by gas chromatography in 24-hour urine samples obtained once weekly from 76 randomly selected pregnant women 21,28,35, and 42 days after the last menstrual period. Pregnancy was ascertained by a positive hemagglutination inhibition test for human chorionic gonadotropin. In patients in whom the urinary pregnanediol content was less than 3 mgl24 hours the abortion rate was 81.5%, and 18.5% had normal pregnancies and births. In patients whose pregnanediol content was greater than 3 mgl24 hours the abortion rate was 8.3%, and 91.7% had normal pregnancies and births. The 24-hour urinary pregnanediol excretion rate reflects corpus luteum function and can be considered as a means of monitoring pregnancy in its initial stage.

Many women experience vaginal bleeding during the first trimester of pregnancy. It is estimated that .10% to 15% of all pregnancies terminate in abortion, and in patients treated for infertility the rate approaches 25%. A reliable laboratory test, if performed early enough, might enable a prognosis of the pregnancy to be made as early as 1 week after conception. No such test has hitherto been devised. 1 The aim of the present study was to determine whether the estimation of urinary pregnanediol content during the luteal phase may be of value in establishing the prognosis of pregnancy. We chose pregnanediol as our criterion, notwithstanding the reservations expressed by other investigators,2, 3 since the method of pregnanediol assay has undergone considerable refinement. 4 ,5

MATERIALS AND METHODS

Seventy-six patients were selected at random from the infertility clinics and the habitual abortion clinic at Zahalon Government Hospital, Tel Aviv, Israel. Only patients in whom pregnancy was diagnosed by sustained elevated basal body temperature and positive hemagglutination inhibition tests were included in the study. No attempt was made to group the patients according to treatment received, since this would have been irrelevant to the prospective aim of the study, and no therapeutic conclusions were drawn. Each patient was followed until termination of pregnancy. Urine samples were collected over 24 hours on days 21, 28, 35, 42 following the 1st day of the last menstrual period. The pregnanediol content was estimated by using the extraction method of J ayle4 and the gas chromatographic method described by Nair et al. 5 The latter method was modified slightly to incorporate an intra-assay standard which in no w~y affected either the

Received March 13, 1977; revised July 7, 1977, and September 19, 1977; accepted October 3, 1977. *Reprint requests: Samuel Levin, M.D., Department of Obstetrics and Gynecology, Donolo-Zahalon Government Hospital, Tel Aviv-Jaffa, Israel.

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February 1978

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FIG. 1. Mean values and standard deviation of urinary pregnanediol in pregnancies which terminated in normal delivery (upper curve) and in pregnancies which resulted in spontaneous abortion (lower curve).

specificity of the gas chromatographic process or its accuracy. The coefficient of variation was less than 8% for values between 1 and 10 mg/24 hours. For statistical analysis of the results the Least Squares method and the correlation coefficient (r) was used. 6

tween the abortion rates in the two groups and between the rates of delivery at term in the two groups were highly significant. . In the six pregnancies resulting in twin delivery, urinary pregnanediol values were greater than 13 mg/24 hours during the first 6 weeks of pregnancy .

RESULTS

DISCUSSION

In all patients, urinary pregnanediol values obtained before expected menstruation, i.e., on days 21 and 28 of the menstrual cycle, were recorded. Patients were divided into two groups* on the basis of these results: group I included patients with urinary pregnanediol concentrations of less than 3 mg/24 hours (25 patients); group II included patients with urinary pregnanediol concentrations of more than 3 mg/24 hours (45 patients). Figure 1 shows the mean urinary pregnanediol values in both groups. In group I, pregnanediol values showed little change during the first 6 weeks of pregnancy, whereas the patients in group II showed a steady increase in pregnanediol levels. The outcome of pregnancy was found to be related to pregnanediol excretion in these groups. In group I the abortion rate was 81.5%, and only 18.5% of pregnancies proceeded to term; in group II the abortion rate was 8.3%, and 91.7% ofpregnancies proceeded to term. The differences be-

The mode of action of progesterone and its function in pregnancy are not yet fully understood, but its presence seems to be vital to the normal progress of pregnancy.7 The corpus luteum is thought to be the principal source of progesterone in the early stages of pregnancy. Yoshimi et aLB reported that progesterone secretion by the corpus luteum of pregnancy is greatest during the 6 weeks following ovulation. This finding prompted us to re-examine the possibility of using urinary pregnanediol levels to monitor corpus luteum activity, since pregnanediol is the main urinary metabolite of progesterone and its secretion is positively correlated with, and accurately reflects, that of progesterone during both the menstrual cycle and pregnancy.9. 10 The use of pregnanediol estimation for the purpose of pregnancy prognosis was first recorded in 1950, when Guterman l l reported an abortion rate of 90% in women with low urinary pregnanediol levels. However, the test walYnot widely accepted for clinical application, since other researchers

*Patients who later delivered twins were excluded from the two groups.

Vol. 29, No.2

URINARY PREGNANEDIOL ESTIMATION FOR MONITORING PREGNANCY

such as Klopper12 and Shearman3 found no correlation between urinary pregnanediol content and subsequent pregnancy development. The lack of correlation as observed by these authors may have been due to improper timing of sample collection. Furthermore, the accuracy of gas chromatography now allows renewed consideration of this method in monitoring pregnancy in the early stages. Although radioimmunoassay of plasma progesterone is known to be a reliable prognostic procedure, its use is restricted to laboratories with specialized and expensive equipment whose services are not always easily available. Since urinary pregnanediol values and plasma progesterone levels have been shown to be positively correlated, one may as safely rely on the easily performed pregnanediol tests as on progesterone determination to monitor corpus luteum activity. Most of the abortions in our series appear to have resulted from primary or secondary corpus luteum insufficiency. The highly significant differences between the abortion rates and between the rates of pregnancies carried to term in the two groups strongly suggest that an early prognosis of pregnancy can be made on the basis of urinary pregnanediol estimation. An interesting finding was the high pregnanediol levels observed in the six twin pregnancies. A similar finding was mentioned by Bengtsson and Ejarque. 13 These results deserve further investigation, with the possibility of developing a method of early diagnosis of multiple births.

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WB Saunders Co., 1973, p 916 2. Goldzieher JW, Benigno BB: The treatment of threatened and recurrent abortion: a critical review. Am J Obstet Gynecol 75:1202, 1958 3. .shearman RP: Some aspects of the urinary excretion of pregnanediol in pregnancy. J Obstet Gynaecol Br Emp 66:1,1959 4. Jayle MF: Analyse des Steroides Hormonaux, Vol 2. Paris, Masson et Cie, 1962, p 285 5. Nair PP, Sarlos IJ, Solomon D, Turner DA: Simultaneous separation of 17-ketosteroids and estrogens by biphase gas chromatography. Anal Biochem 7:96, 1964 6. Moroney MJ: Facts from Figures, Third Edition. London, Pelican, 1956, p 277 7. Csapo A: The role of progesterone in the maintenance and determination of pregnancy. In Progesterone and the Defense Mechanism of Pregnancy. Ciba Foundation Study Group No 9. London, Churchill, 1961, p 7 8. Yoshimi T, Strott CA, Marshall JR, Lipsett MB: Corpus luteum function in early pregnancy. J Clin Endocrinol Metab 29:225, 1969 9. Deshpande GN, Turner AK, Sommerville IF: Plasma progesterone and pregnanediol in human pregnancy, during labour and post-parturn:. J Obstet Gynaecol Br Emp 67: 954, 1960 10. Arcos M, Gurpide E, Vande Wiele RL, Leberman S: precursors of urinary pregnanediol and their influence on the determination of the secretory rate of progesterone. J Clin Endocrinol Metab 24:237,1964 11. Guterman HS: The physiologic basis for clinical applications of progesterone. J Clin Endocrinol Metab 10:641, 1950 12. Klopper AI: Endocrine factors in abortion and premature labor. In Endocrinology of Pregnancy, Edited by F Fuchs, AI Klopper. New York, Harper and Row, 1971, p 332 13. Bengtsson LP, Ejarque PM: Production rate of progesterone in the last month of human pregnancy. Acta Obstet Gynecol Scand 43:49, 1964