Serum progesterone testing to predict ectopic pregnancy in symptomatic first-trimester patients

doi:10.1067/mem.2000.108653

Annals of Emergency Medicine

Volume 36, Issue 2, August 2000, Pages 95-100

https://doi.org/10.1067/mem.2000.108653 Get rights and content

Abstract

Study Objective: This study was conducted to prospectively measure the accuracy of serum progesterone levels to detect ectopic pregnancy. Methods: Seven hundred sixteen symptomatic first-trimester emergency department patients with abdominal pain or vaginal bleeding at a tertiary care military teaching hospital had progesterone levels measured by radioimmunoassay with results unavailable to the treating physician. All patients were monitored until a criterion standard diagnosis of intrauterine pregnancy or ectopic pregnancy was confirmed. Results: A 14-month derivation phase (n=399) used receiver operating characteristic curve testing to select a cutoff value of progesterone less than 22 ng/mL. A 12-month validation phase (n=317) then retested this cutoff value. Combining both phases, there were 434 (61%) viable intrauterine pregnancies, 229 (32%) nonviable intrauterine pregnancies, and 52 (7.3%) ectopic pregnancies, of which 17 were ruptured. Sensitivity, specificity, positive predictive values, and negative predictive values (95% confidence intervals) for progesterone levels less than 22 ng/mL to detect ectopic pregnancy were 100% (94% to 100%), 27% (23% to 30%), 10% (7% to 12%), and 100% (98% to 100%), respectively. Conclusion: Given similar disease prevalence, roughly one fourth (178/716) of symptomatic patients can be classified as low risk (0%, 95% confidence interval 0 to 2%) for having an ectopic pregnancy using a progesterone cutoff of 22 ng/mL. Whether implementation of rapid progesterone testing can safely expedite care and reduce the need for urgent diagnostic evaluation or admission remains to be determined. [Buckley RG, King KJ, Disney JD, Riffenburgh RH, Gorman JD, Klausen JH. Serum progesterone testing to predict ectopic pregnancy in symptomatic first-trimester patients. Ann Emerg Med. August 2000;36:95-100.]

Introduction

Ectopic pregnancy is the leading cause of pregnancy-related death in the first trimester¹ and a common primary care and emergency department diagnostic and management dilemma. The incidence of ectopic pregnancy increased more than fourfold from 1970 to 1992, with the Centers for Disease Control and Prevention estimating that almost 2% of all pregnancies are ectopic.2, 3 The yearly economic cost of ectopic pregnancy was estimated in 1990 to exceed $1.1 billion.⁴ Early diagnosis, therefore, is crucial, both to reduce morbidity and mortality and to reduce the risk of future infertility.

Previous studies have shown that the serum progesterone level is a potentially useful laboratory marker for ectopic pregnancy. Many of these studies were either selected case series,5, 6, 7 retrospective in design,8, 9 or used progesterone cutoff levels less that 20 ng/mL.10, 11, 12 In the largest prospective study to date, with more than 1,900 patients enrolled, Stovall et al¹³ found that a progesterone level less than 25 ng/mL had a sensitivity of 97% and a specificity of 62%. This study, despite limitations and a relatively high rate of patients lost to follow-up, demonstrated the potential role of progesterone level as a screening test. Similar conclusions were reached in a recent meta-analysis, which found that, although lacking adequate specificity to predict the presence of ectopic pregnancy, the progesterone level was sensitive enough at higher cutoff values to virtually exclude the diagnosis.¹⁴

To further characterize the ability of the serum progesterone level to predict the presence or absence of ectopic pregnancy in symptomatic ED patients, we assembled a prospective clinical data registry with follow-up of all patients until a criterion standard pregnancy diagnosis was established. In the first phase of our study, we derived a maximally sensitive cutoff value.¹⁵ We then independently validated our findings in a second group of patients. By measuring the accuracy of serum progesterone testing, we hope to better define the role that such testing may play in the ED management of first-trimester patients at risk of ectopic gestation.

Section snippets

Materials and methods

All patients presenting to the ED at Naval Medical Center San Diego between August 1, 1994, and September 30, 1996, with abdominal pain or vaginal bleeding in the first trimester of pregnancy, were prospectively entered into a clinical data registry. Naval Medical Center San Diego is a tertiary care teaching hospital with an annual ED census of approximately 60,000 patients. We excluded all patients with prior documentation of an intrauterine pregnancy (IUP) on pelvic ultrasonography and those

Results

Between August 1994 and October 1996, 1,047 patients presenting to the ED with the chief complaint of abdominal pain with or without vaginal bleeding were prospectively enrolled in a clinical data registry. One hundred fourteen patients were excluded: 2 because of hemodynamic instability, 74 because of previously documented IUP, and 38 because of incomplete coding of key clinical data elements (such as pain history or abdominal or pelvic findings). Of the remaining 933, 18 (1.9%) were lost to

Discussion

From a prospective cohort of 718 symptomatic first-trimester patients, we found that no patient with an ectopic pregnancy had a progesterone level greater than 22 ng/mL. The resulting sensitivity of 100% and a specificity of 26.8%, therefore, allow for roughly one fourth of all symptomatic first-trimester patients to be classified as being at low risk (95% CI 0 to 2%) of having an ectopic pregnancy.

Our findings are similar to those of earlier investigators. Three previous prospective studies

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Cited by (30)

Biomarkers for ectopic pregnancy and pregnancy of unknown location
2013, Fertility and Sterility
Citation Excerpt :
Further studies are needed to replicate these findings and move this promising marker from phase III to phase IV of development. As a readily available clinical assay, P has been extensively studied as a potential marker of early pregnancy failure and EP, both as a single marker and in combination (29, 30, 34, 37, 42, 52–77). A meta-analysis of 26 studies suggested that serum P <5 ng/mL had good prediction for non-viable pregnancies, but was unable to differentiate EPs from aIUPs (75).
Early pregnancy failure is the most common complication of pregnancy, and 1% to 2% of all pregnancies will be ectopic. As one of the leading causes of maternal morbidity and mortality, diagnosing ectopic pregnancy and determining the fate of a pregnancy of unknown location are of great clinical concern. Several serum and plasma biomarkers for ectopic pregnancy have been investigated independently and in combination. The following is a review of the state of biomarker discovery and development for ectopic pregnancy and pregnancy of unknown location.
Single point biochemical measurement algorithm for early diagnosis of ectopic pregnancy
2013, Clinical Biochemistry
Citation Excerpt :
Our findings were consistent with some other studies [27,46,47] including a meta-analysis of 26 studies [30], in which progesterone failed to discriminate between ectopic pregnancy and spontaneous miscarriage. Buckley et al. [48] found a sensitivity of 100% for ectopic pregnancy at a cutoff of 22 ng/mL but, at our similar cutoff of 20.4 ng/mL (Table 3), we found a sensitivity of only 65% for ectopic pregnancy. Overall, despite the significant all-pairwise Kruskal–Wallis results (Table 2), ROC analyses revealed that the performance of progesterone was poor, compared to the other markers (Fig. 2 and Table 3).
Tubal rupture as a result of an ectopic pregnancy is the leading cause of first trimester maternal mortality. Currently, the diagnosis of ectopic pregnancy depends on transvaginal ultrasound and serial serum measurements of human chorionic gonadotrophin (hCG), which requires follow up. The objective of this study was to examine whether single point measurements at presentation could distinguish between women with ectopic pregnancy, viable pregnancy, and spontaneous miscarriage.
Serum total hCG (hCGt), hyperglycosylated hCG (hCGh), free beta subunit of hCG (hCGβ), progesterone (P), and CA-125 were measured by chemiluminescence immunoassay over a 3 month period in 441 women presenting at the emergency room with abdominal pain and a positive pregnancy test. Patient outcomes were followed and confirmed by histology. 65 samples were excluded due to poor sample storage, or lost to follow up.
The pregnancy outcomes were 175 viable pregnancies, 175 spontaneous miscarriages, and 26 ectopic pregnancies. A serum hCGt < 3736 mIU/mL cut off was 100% sensitive, with 76% specificity, for distinguishing ectopic pregnancy from viable pregnancy; but did not differentiate spontaneous miscarriage. Serum CA125 < 41.98 U/mL produced 100% sensitivity and 43% specificity in distinguishing ectopic pregnancy from spontaneous miscarriage. Sequential application of hCGt and CA-125 cut off followed by ultrasound could detect 100% of ectopic pregnancies with 87% specificity for all intrauterine pregnancies.
The combination of serum hCGt < 3736 mIU/mL, followed by CA125 < 41.98 U/mL is a promising algorithm for detecting all ectopic pregnancy at initial presentation.
Predictive value of serum human chorionic gonadotropin ratio, progesterone and inhibin A for expectant management of early pregnancies of unknown location
2012, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Recent data indicate that low serum progesterone (s-progesterone) levels correlate with spontaneously resolving pregnancy [6–9] and very low values (<10 nmol/l) at presentation may safely predict spontaneous resolution of PUL [9]. This parameter has been suggested for use in conjunction with s-hCG in order to improve diagnostic efficacy [5,7,8,10–16]. Low s-inhibin A is another potential predictor of spontaneously resolving PUL [2,12].
To evaluate serum human chorionic gonadotropin (hCG) ratio, progesterone and inhibin A as single parameters and in combination for the prediction of spontaneous resolution of pregnancies of unknown location (PUL).
Prospective observational study of 105 consecutive patients with a diagnosis of PUL. Serum levels of hCG, progesterone and inhibin A were determined at the first visit and after 2 days. Patients were followed clinically until a final diagnosis of spontaneously resolving PUL, viable or non-viable intrauterine pregnancy, or ectopic pregnancy with need of laparoscopic intervention had been reached. Different combinations of hCG ratio (hCG at 48 h/hCG at 0 h), s-progesterone and s-inhibin A were investigated to find the best predictor for successful expectant management.
The final pregnancy outcomes were: 52 spontaneously resolving PUL (49.5%), 37 viable intrauterine pregnancies (35.2%), 8 non-viable intrauterine pregnancies (7.6%), 7 ectopic pregnancies (6.7%), and one molar pregnancy (1.0%). An hCG ratio < 0.80 predicted spontaneously resolving PUL with positive and negative predictive values (PPV and NPV), sensitivity, and specificity of 0.98, 0.78, 0.72, and 0.99, respectively. In patients with hCG ratio ≥ 0.80, a combination of s-progesterone < 20 nmol/l and s-inhibin A < 30 pg/ml predicted spontaneously resolving PUL with PPV, NPV, sensitivity and specificity of 0.92, 0.96, 0.85, and 0.98 respectively.
Our results suggest that patients with PUL and hCG ratio < 0.80 display a high probability of spontaneously resolving PUL with minimum need of follow-up. In cases of hCG ratio ≥ 0.80, a combination of s-progesterone < 20 nmol/l and s-inhibin A < 30 pg/ml, may be a reliable predictor of spontaneously resolving PUL. The safety of this approach should be tested in large prospective studies.
Ectopic Pregnancy
2008, Pediatric Emergency Medicine
Ectopic Pregnancy
2007, Pediatric Emergency Medicine
Receiver operator characteristics and diagnostic value of progesterone and CA-125 in the prediction of ectopic and abortive intrauterine gestations
2006, European Journal of Obstetrics and Gynecology and Reproductive Biology
The study was designed to investigate the predictive value of progesterone and CA-125 in the diagnosis of ectopic pregnancy (EP) and inevitable miscarriage.
Forty women with EP, 20 with intrauterine (IU) abortive gestation and 20 regular pregnant women (controls) were studied. IU abortive and EP were confirmed and treated by surgery. Serum progesterone and CA-125 levels were measured at the time of presentation and 24 h after surgery.
Women with EP had significantly lower progesterone concentrations, compared to both women with IU abortive pregnancy and controls. Women with IU abortion had significantly higher CA-125 levels, compared to the other two groups. When using a progesterone concentration of less than 10.75 ng/ml as a cut-point for the diagnosis of EP, sensitivity, specificity, positive and negative predictive values were 85%. When using CA-125 concentration of more than 41.9 U/ml as a threshold for the diagnosis of IU abortive pregnancy, sensitivity was 80%, specificity 87%, the positive predictive value was 66% and the negative predictive value 93%.
The measurement of progesterone and CA-125 levels is useful in discriminating ectopic and intrauterine abortive from normal gestations.

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^*: The Chief, Bureau of Medicine and Surgery, Navy Department, Washington, DC, Clinical Investigation Program, sponsored this report No. 84-16-1968-897 as required by NSHSBETHINST 6000.41A.

^**: The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States government.

^*: Address for reprints: CDR Robert G. Buckley, MC, USN, Naval Hospital Rota Spain, PSC 819, Box 18, NH #104, FPO, AE 09645-5018; 011-34-956-82-3308, fax,011-34-956-82-3306; E-mail,[email protected].

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Original ContributionsSerum progesterone testing to predict ectopic pregnancy in symptomatic first-trimester patients*,**,*

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Fertil Steril

Fertil Steril

Fertil Steril

Fertil Steril

Fertil Steril

Ann Emerg Med

Ann Emerg Med

Maternal mortality surveillance, United States, 1979-1986

Morb Mortal Wkly Rep CDC Surveill Summ.

Epidemiology of ectopic pregnancy

Clin Obstet Gynecol

Ectopic pregnancy—United States, 1990-1992

MMWR Morb Mortal Wkly Rep

Original Contributions
Serum progesterone testing to predict ectopic pregnancy in symptomatic first-trimester patients*,**,*