Plasma Progesterone Levels in Normal and Abnormal Early Human Pregnancy*

Vo\. 30, No.4, October 1978 Printed in U.S.A.

FERTILITY AND STERILITY Copyright" 1978 The American Fertility Society

PLASMA PROGESTERONE LEVELS IN NORMAL AND ABNORMAL EARLY HUMAN PREGNANCY*

EWA RADWANSKA, M.D., M.R.C.O.G.t JOHN FRANKENBERG, F.R.C.O.G. ELIZABETH I. ALLEN, B.S.

University College Hospital, London and Hillingdon Hospital, Uxbridge, England

Plasma progesterone levels were measured by a competitive protein-binding method (Radwanska E, Swyer GIM: J Obstet Gynaecol Br Commonw 81:107, 1974) in 224 women during the first trimester ofpregnancy-127 in normal pregnancy, 66 hospitalized with symptoms of threatened abortion, 10 with missed abortion, 11 with ectopic pregnancy, and 10 with incomplete abortion. In normal early pregnancy (6 to 12 weeks), plasma progesterone levels ranged from 10 to 54 nglml (mean ± standard deviation: 25.5 ± 10.3 nglml; n = 158). In cases of threatened abortion between 6 and 12 weeks in which pregnancy progressed successfully to term, the first-trimester plasma progesterone levels ranged from 5 to 42 nglml (22.5 ± 92 nglml; n = 25)-not significantly different from normal pregnancies. In women with threatened abortion who subsequently aborted, they ranged from 3 to 48 nglml (14.1 ± 9.9 nglml; n = 77)significantly lower (P <0.001) than the mean for normal pregnancies and for those patients with threatened abortion whose pregnancies continued. In cases of missed abortion, the plasma progesterone level ranged from 3 to 12 nglml (7.0 ± 2.0 nglml; n = 18), suggestive of defective pregnancy. In all 10 cases admitted to the hospital with incomplete abortions the plasma progesterone level was below 2 nglml, confirming the clinical findings. The diagnosis of early pregnancy abnormalities, especially in clinically more difficult cases, was greatly facilitated by the use of plasma progesterone estimation, a low progesterone level usually indicating nonviable pregnancy. Fertil Steril 30:398, 1978

In 1969 Johansson 1 established the range of plasma progesterone levels in normal pregnancies and also reported the levels found in 11 patients who aborted spontaneously. In many of these unsuccessful pregnancies the plasma progesterone values were below the normal range, suggesting that low progesterone levels might be diagnostic for defective pregnancies, at least in

some cases. In cases of early pregnancy complications, it is of considerable clinical importance to be able to differentiate, using noninvasive techniques, between viable intrauterine pregnancies which are likely to continue and those in which the conceptus is nonviable and evacuation of the uterus is desirable. Monitoring the progress of pregnancy in patients with threatened abortion by clinical observation is of limited value. Commercial pregnancy tests are not always reliable as they may remain positive or doubtful in up to 40% of cases for up to 5 days, even after termination of pregnancy.2 Ultrasonic techniques may be accurate in the diagnosis of pregnancy in approximately 80% of cases of bleeding during the first trimester 3 but provide no information on the

Received October 13, 1977; revised April 3, 1978; accepted June 2, 1978. *Presented at the Thirty-Fourth Annual Meeting If The American Fertility Society, March 29 to April 1, 1978, New Orleans, La. tPresent address and address for reprint requests: Department cf Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, N. C. 27514.

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PLASMA PROGESTERONE LEVELS IN HUMAN PREGNANCY

functional status of the trophoblast. Vaginal smears, although showing higher-than-normal pyknotic indices in some cases of disturbed pregnancies, have not been convincingly shown to have reliable prognostic value. 4 Estimation ofpregnanediol excretion as a measure of progesterone production is subject to severe practical and theoretical limitations, and its use in the management of threatened abortion has largely been abandoned. For these reasons, measurements of blood levels of hormones such as progesterone and human chorionic gonadotropin, which are directly involved in the maintenance of early pregnancy have been gaining popularity in evaluating the events during both normal 2 • 4. 5 and complicated pregnancies.4-8 In the hope that plasma progesterone estimation might be of diagnostic and prognostic value in complications of the first trimester of pregnancy (i.e., threatened abortion, missed abortion, and ectopic pregnancy) we have studied plasma progesterone levels in both normal early pregnancies and in patients in whom abnormality was suspected, and have endeavored to correlate these findings with the ultimate outcome of the pregnancy. MATERIALS AND METHODS

Three hundred and six blood samples were obtained from two hundred and twenty-four women who were attending the fertility, gynecology, and antenatal clinics of University College Hospital, London and Hillingdon Hospital, Uxbridge, or who were admitted to the hospital during emergency situations and in whom the presence of early pregnancy was presumed or suspected. Plasma progesterone levels were measured by a rapid radiocompetitive protein-binding method, essentially that of Johansson,9with minor modifications described elsewhere. lO

RESULTS

Altogether, 158 plasma progesterone estimations were performed in 127 women during normal early pregnancies (6 to 12 weeks from the date of the last menstrual period); this group included 50 patients requesting therapeutic abortion for nonmedical reasons and 77 patients with uncomplicated pregnancies which subsequently resulted in the full-term birth of single live infants. Among these 77 patients who successfully

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completed pregnancies, 9 had a history of habitual abortion, 36 had previous infertility problems (women in whom pregnancy followed induction or stimulation of ovulation with agents such as clomiphene or gonadotropins are not included in this series), and 32 represented a sample of the normal population. In the remaining 97 patients who represented complications of early pregnancy, 148 progesterone estimations were performed: in 66 cases of threatened abortion (clinical diagnosis), in 10 cases of missed abortion (suspected clinically and subsequently confirmed by dilatation, curettage, and microscopic examination), in 11 cases of ectopic pregnancy (usually suspected on admission, when the blood was obtained for plasma progesterone estimation, and later confirmed by laparotomy), and in 10 cases of incomplete abortion (clinical diagnosis on admission, later confirmed by microscopic examination of evacuated residual products of conception). In normal early pregnancy (6 to 12 weeks), plasma progesterone levels ranged from 10 to 54 ng/ml (mean ± standard deviation: 25.5 ± 10.3 ng/ml; n = 158) and were rising slowly throughout the first trimester (Fig. 1). The analysis of plasma progesterone values during uneventful pregnancies showed no significant difference fP· > 0.3) between levels encountered at the same gestational age in completely normal, unselected populations (patients in the "booking" antenatal clinic and patients undergoing therapeutic abortions) and those in patients with -a previous history of infertility or habitual abortion (all these patients had full-term live birth as an outcome of

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the pregnancies under consideration). Therefore, individual data on all those normal pregnancies are presented jointly in Figure 1. Because of enormous overlap of normal values during 6 to 12 weeks, these values were combined in Figure 2 (mean ± standard deviation: 25.5 ± 10.3 ng/ml). In cases of threatened abortion between 6 and 12 weeks in which pregnancy progressed successfully to term, the first-trimester plasma progesterone levels (usually measured when the patient was first examined in the clinic or on admission to the hospital with evidence of vaginal bleeding in the presence of pregnancy-as diagnosed by pregnancy testing and, in more doubtful cases, by ultrasound examination) ranged from 5 to 42 ng/ml (22 ± 9.2 ng/ml; n = 25); the values for •

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October 1978

these otherwise successful pregnancies were not significantly different (P- >0.2) from those in normal pregnancies (Figs. 2 and 3) . In women with signs of threatened abortion who subsequently aborted (usually within a few days of admission), progesterone values ranged from 3 to 48 ng/ml (14.1 ± 9.9 ng/ml; n = 77), the mean value being significantly lower (P < 0.001) than the mean for normal pregnancies and for those women with threatened abortion whose pregnancies continued to term (Figs. 2 and 3). Most of these patients showed abnormally low (or falling) levels of plasma progesterone; on the other hand, several patients aborted in spite of normal progesterone levels at the time of blood sampling. This appears to indicate a greater diagnostic and prognostic value of low rather than normal pregesterone levels in cases of threatened abortion. In cases of missed abortion (diagnosed on the basis of uterine size-date discrepancy, failure of the uterus to enlarge, often doubtful pregnancy test, and failure of ultrasound examination to confirm a developing pregnancy-with or without slight vaginal bleeding) plasma progesterone levels ranged from 2 to 13 ng/ml (6.2 ±3.6 ng/ml; n = 18), the mean value being significantly lower (P < 0.001) than that in developing pregnancies. Individual results showed only slight overlap with the lower range of values obtained in normal pregnancies (Figs. 2 and 3). In patients with the ultimate diagnosis of ectopic (tubal) pregnancy-those admitted to the hospital with abdominal pain and menstrual disturbance and those who were asymptomatic at the time of blood sampling for plasma progesterone measurements performed in early pregnancy as a part of their management (e.g., patients attending the fertility clinic)-plasma progesterone levels ranged from 3 to 12 ng/ml(7.0 ± 2.0 ng/ml; n = 18), again significantly below normal and suggestive of defective pregnancy . In all patients admitted to the hospital with incomplete abortion and subjected to routine evacuation of the retained parts of conceptus, the plasma progesterone level was below 2 ng/ml (n = 10), confirming the clinical findings. It was clear that plasma progesterone values lo~er than 10 ng/ml (with the exception of one patient with threatened abortion who had one value of 5 ng/ml but subsequently showed normal results) were inevitably associated with abnormal pregnancy and unfavorable outcome; this was a particularly striking feature of some patients

October 1978

PLASMA PROGESTERONE LEVELS IN HUMAN PREGNANCY

with missed abortion and asymptomatic ectopic pregnancy in whom serial plasma pregesterone assays were performed and low values were found repeatedly. With more experience, as the incidence of intrauterine defective pregnancies presenting as "missed abortion" and ectopic pregnancies appeared similar in this series, it was thought that laparoscopy was justified in patients in whom plasma progesterone levels were repeatedly low in early pregnancy. In this way, two of three ectop c pregnancies which occurred in previously infertile patients from the fertility clinic were diagnosed laparoscopically and treated before the onset of clinical symptoms. On the other hand, a normal progesterone level in the presence of bleeding in early pregnancy, although reassuring and normally found in pregnancies with a favorable outcome, was also commonly seen in cases of threatened abortion terminating in miscarriage. It was concluded that low plasma progesterone values are of great diagnostic and prognostic value in indicating nonviable pregnancy and facilitating clinical management in such cases; normal values do not preclude the possibility of pregnancy wastage and have less prognostic significance. However, a plasma progesterone level in the upper normal range in early pregnancy in the presence of slight vaginal bleeding appears to make the possibility of ectopic pregnancy very unlikely and is an important diagnostic consideration. DISCUSSION

The values of plasma progesterone in normal early pregnancies in our series are in agreement with those reported by other investigators.!' 5 Interestingly, they also appear normal during successful pregnancies in patients with the history of repeated abortions and in cases of threatened abortion which progressed to term. This would indicate that, if luteal phase defects playa role in repeated pregnancy wastage (as they seem to be able to prevent conceIt ion l l ), successful pregnancies in women prone to such defects result from cycles with adequate corpus luteum formation and function, followed by successful lu teoplacental "shift." In pregnancies which are not developing satisfactorily (presenting as threatened abortion or suspected of missed abortion) and which are aborted or evacuated, plasma progesterone levels tend to be low, indicating, in our

401

opinion, that at that point the pregnancy is already beyond salvage. A reduction in hormone production by the corpus luteum appears to be the effect rather than the cause of abortion. In this context no support could be given to substantiate the use of synthetic gestagens, as well as progesterone, in the treatment of threatened abortion. This view appears to predominate in the literature on this subject. 12' 16 Concurrently with our study other investigators have also found that hormonal assays such as measurements of progesterone, 17 a-hydroxyprogesterone, prolactin, estradiol, and human chorionic gonadotropin (HCG) provide indices of the function of the fetoplacental unit in early pregnancies, low levels of these hormones correlating well with the adverse outcome ofpregnancy.6. 8. 17 Of particular interest is the finding that in ectopic pregnancy the fetoplacental unit appears to be dysfunctional, presumably affected by the adverse conditions at implantation site in the fallopian tube. This is reflected by uniformly low plasma progesterone levels in these cases-a fact of potentially great diagnostic importance. Three other reports 7. 18, 19 on hormonal measurements in ectopic pregnancy have also been able to demonstrate this abnormality as a characteristic feature of extrauterine gestation (Milwidsky et al,7 by finding progesterone values lower than normal, with HCG values correlating rather poorly with plasma progesterone; Saxena and Landesman 18 and Sroga 19 by finding low HCG levels in cases of tubal pregnancy). In conclusion, measurement of the plasma progesterone levels in patients with complications ofthe first trimester of pregnancy can facilitate the diagnosis of a nonviable pregnancy, including ectopic gestation and impending abortion, when the progesterone level is found to be below those encountered during normal pregnancies (in our hands, below 10 ng/mI). On the other hand, the prognostic val ue of progesterone measurement in cases in which it appears normal is less certain. Many such patients carry pregnancies to term, but some abort, possibly because of other factors. However, it is our feeling that pregnancies associated with normal progesterone levels are potentially salvageable and in such patients general measures employed in the treatment of threatened abortion are justified. Serial progesterone estimations are, of course, of greater value than a single testing, especially when the initial value is borderline. Further studies are needed to determine the etiology and the best management

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of threatened and/or repeated abortions, but it appears that an assessment of the hormonal status as reflected by the blood levels of HCG and progesterone in every case of early pregnancy abnormality provides very useful information and should be treated as a guide in the clinical management. REFERENCES 1. Johansson EDB: Plasma levels of progesterone in pregnancy measured by a rapid competitive protein binding technique. Acta Endocrinol (Kbh) 61:607,1969 2. Saunders DM, Kelso 1M: Hormonal parameters following termination of pregnancy: a guide to the management of threatened abortion. Am J Obstet Gynecol 120: 1118, 1974 3. Kukard RFP, Coetzee M: A comparison between ultrasonic and clinical diagnostic reliability in early pregnancy complications. S Afr Med J 48:2109,1974 4. Khanna I, Radwanska E, Swyer GIM: Comparison of vaginal cytology with plasma progesterone levels in human pregnancy. Indian J Med Res 64:1267, 1976 5. Dawood MY: Circulating maternal serum progesterone in high-risk pregnancies. Am J Obstet Gynecol 125:832, 1976 6. Kunz J, Keller PJ: HCG, HPL, oestradiol, progesterone and AFP in serum in patients with threatened abortion. Br J Obstet Gynaecol 83:640, 1976 7. Milwidsky A, Adoni A, Segal S, Palti Z: Chorionic gonadotropin and progesterone levels in ectopic pregnancy. Obstet Gynecol 50:145, 1977 8. Nygren KG, Johansson EDB, Wide L: Evaluation of the prognosis of threatened abortion from the peripheral plasma levels of progesterone, estradiol, and human chorionic gonadotropin. Am J Obstet Gynecol 116:916, 1973

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9. Johansson EDB: Progesterone levels in peripheral plasma during the luteal phase of the normal human menstrual cycle measured by a rap d competitive protein binding technique. Acta Endocrinol (Kbh) 61:592, 1969 10. Radwanska E, Swyer GIM: Plasma progesterone estimation in infertile women and in women under treatment with clomiphene and chorionic gonadotrophin. J Obstet Gynaecol Br Commonw 81:107, 1974 11. Radwanska E, McGarrigle HHG, Swyer GIM: Plasma progesterone and oestradid estimations in the diagnosis and treatment of luteal insufficiency in menstruating infertile women. Acta Eur Fertil 7:39, 1976 12. Swyer GIM: Progestogens and their clinical uses. Br Med J 1:48, 1960 13. Klopper A, MacNaughton M: Hormones in recurrent abortion. J Obset Gynaecol Br Commonw 72:1022, 1965 14. Swyer GIM, Little V: Progestational agents and disturbances of pregnancy. J Obstet Gynaecol Br Commonw 72:1014, 1965 15. Johannsen A: Threatened and spontaneous abortion. A retrospective study of the diagnosis and admission. Acta Obstet Gynecol Scand 49:95,1970 16. Nygren KG, Johansson EDB: The effect of norethindrone and some other synthetic gestagens upon the peripheral plasma levels of progesterone and estradiol during early human pregnancy. Acta Obstet Gynecol Scand 54:57, 1975 17. Jovanovic L, Daweod MY, Landesman R, Saxena BB: Hormonal profile as a prognostic index of early threatened abortion. Am J Obstet GynecoI130:274, 1978 18. Saxena BB, Landesman R: The use of radioreceptorassay cf human chorionic gonadotropin for the diagnosis and management of ectopic pregnancy. Fertil Steril 26:397, 1975 19. Sroga W: The quantitative estimation of urinary chorionic gonadotropin in women with ectopic pregnancy. Ginekol Pol 46:23, 1975