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Use of a sensitive urine pregnancy test before endometrial biopsies taken in the late luteal phase
FERTILITY AND STERILITY
Vol. 53, No. 1, January 1990
Copyright© 1990 The American Fertility Society
Printed on acid-free paper in U.S.A.
Use of a sensitive urine pregnancy test before endometrial biopsies taken in the late luteal phase Carl M. Herbert, M.D.*t George A. Hill, M.D.* Wayne S. Maxson, M.D.:j:
Anne Colston Wentz, M.D.§ Kevin G. Osteen, Ph.D.*
Center for Fertility and Reproductive Research, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee
Endometrial biopsies taken during the late luteal phase are an important part of evaluating patients presenting with infertility, recurrent spontaneous abortion, and those undergoing ovulation induction. The late luteal phase endometrial biopsy should be taken 1 to 2 days before the onset of menses. An endometrial biopsy obtained during this time carries a theoretical risk of interrupting an early pregnancy that may have occurred during this cycle. Considering this risk many physicians have advised patients scheduled for an endometrial biopsy to either refrain from exposure or use barrier contraception during that cycle. These options, although effective, are not always well accepted or followed by patients anxious for every chance to conceive and already frustrated by multiple previous manipulations. In addition, the late luteal phase biopsy is interpreted according to the onset of the next menses. When contraception practices are not used and cycle of conception endometrial biopsies are obtained, they cannot be adequately evaluated. Several authors have examined the rate of spontaneous abortion subsequent to an endometrial biopsy during a cycle of conception Received June 12, 1989; revised and accepted September 5, 1989. * Department of Obstetrics and Gynecology, Vanderbilt U niversity Medical Center. · t Reprint requests: Carl M. Herbert, M.D. Center for Fertil· ity and Reproductive Research, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232·2515. :j: Present address: Northwest Center for Fertility and Repro· ductive Endocrinology, Margate, Florida. §Present address: Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois.
162
Herbert et al.
Communications-in-brief
and have not found an increase in miscarriage rates. 1- 5 Nevertheless, if a reliable, simple, rapid test could detect pregnancy in the late luteal phase before a biopsy, it would be advantageous for the patient. A urine pregnancy test using monoclonal technology in an enzyme linked immunoassay is available. Previous urine pregnancy tests have not been accurate for determining low levels of the beta subunit of human chorionic gonadotropin (~-hCG) in the urine during the very early weeks of pregnancy. False negative results from these less accurate tests have made them impractical for clinical evaluation before endometrial biopsies. Similarly, serum ~ hCG evaluations require at least several hours before results can be determined and, therefore, are not optimal for screening patients just before scheduled endometrial biopsies. These limitations have discouraged most physicians from obtaining a pregnancy test before endometrial biopsy.
MATERIALS AND METHODS
A prospective study was performed evaluating all patients presenting for luteal phase endometrial biopsies at the Cent~r for Fertility and Reproductive Research (C-FARR) at Vanderbilt University Medical Center. All patients were required to keep a basal body temperature (BBT) chart before their scheduled biopsy. All biopsies were scheduled to be performed within 2 days of the anticipated onset of menses, i.e., postovulatory day 12 or later. All patients were actively attempting pregnancy and were being treated for various conditions related to infertility. Fertility and Sterility
The monoclonal urine pregnancy test used was the ICON (Hybritech Corporation, San Diego, CA). We found this test to read positive when the serum levels of f1-hCG are in the range of 15 to 25 miU/mL (Second International Standard, 2nd IS). These values are consistent with serum levels achieved during the late luteal phase of a cycle of conception6 and, therefore, this test potentially offers a way of evaluating patients immediately before the endometrial biopsy. The following prospective study was designed to evaluate the efficacy of this form of urine pregnancy test in diagnosing pregnancies before the expected onset of menses and quantitating the serum level at which this test was positive. When patients presented to the clinic on their assigned day for endometrial biopsy, urine and blood specimens were obtained. These were taken to the gynecologic endocrinology laboratory where the urine pregnancy test was immediately performed. Urine pregnancy tests were performed in accordance with the instructions provided by the Hybritech Corporation and results were usually available in 5 to 10 minutes. However, the appearance of any blue coloration on the ICON disc was considered a positive result. Those patients who demonstrated a positive result did not undergo biopsy and the serum specimen was run that day in a radioimmunoassay (RIA) for a quantitative f1-hCG value (2nd IS) (Clinetics, Tustin, CA). Serum specimens from patients with negative urine tests were batch run by RiA at the end of the study or before if a question arose about false negative urine tests. Pregnant patients were followed for the outcomes of their pregnancies. RESULTS
One hundred twenty-four consecutive patients presented for endometrial biopsy over a 6 month period. Of these 124 patients, 11 (8.9%) were ultimately determined to be pregnant at the time they presented for biopsy. Two of the 11 (18%) patients had negative urine ICON tests before their biopsy and, therefore, underwent an endometrial biopsy, but were subsequently found. to be pregnant. These two patients successfully carried their pregnancies to term. Nine of the 11 patients pregnant at the time they presented for their endometrial biopsy were detected by the urine ICON and avoided an endometrial biopsy. All sera from the 113 patients demonstrating a negative urine ICON and normal menses were negative for f1-hCG by RIA. From Vol. 53, No.1, January 1990
Table 1 Day After Thermogenic Shift on BBT and Serum ,8-hCG Value for Each Patient Who Was Pregnant at the Time of Their Planned Endometrial Biopsy
Patient
Days after thermogenic shift
Urine ICON
Serum ,8-hCG miU/mL•
1 2 3 4 5 6
13 13
7
12 12 13
8 9 10 11
+ + + + + + + + +
b
12 12 11
29 40 79 236' 25 9 19 35 28
11 10
22 4.8
"Second IS. b No BBT available. ' Twin gestation.
these data the sensitivity and specificity of this test are 82% and 100%, respectively. The positive predictive value is 100%, and the negative predictive value is 98%. The serum f1-hCG value present in each of these patients is shown in Table 1. Evaluation of the false negative urine ICON results showed one patient with a very low serum f1-hCG value that would be expected to produce a negative result by the standard interpretation of the ICON. On review of the patient's BBT chart, it was determined that she presented only 10 days after the thermogenic shift and was, therefore, felt to have been missed on the basis of being too early in the gestation of her pregnancy. The other patient presented 11 days after the thermogenic shift on her BBT chart but did have a quantitative amount of f1-hCG in the serum that produced a positive ICON in several of the other patients. All pregnant patients who were at least 12 days after thermogenic shift on BBT were diagnosed as positive by the urine pregnancy test. DISCUSSION
The monoclonal technology in conjunction with enzyme linkage has provided new sensitivity to urine pregnancy testing. Employing this technology before endometrial biopsies has proven efficacious in this study by decreasing the incidence of a cycle of conception endometrial biopsy from a possible 8.9% to an actual 1.6%. The urine ICON was interpreted as positive when serum levels were Herbert et al.
Communications-in-brief
163
as low as 9.2 miU/mL (2nd IS) in the serum. This sensitivity will allow physicians to avoid many unnecessary biopsies. The endometrial biopsy taken during a cycle of conception cannot be adequately interpreted and, therefore, is of no benefit to the patient. In addition, a biopsy in the cycle of conception may create some increased risk of disruption of the pregnancy. The rate of patients being pregnant when they present for an endometrial biopsy was 11 of 124 (8.9%) that is consistent with the findings of other studies in the literature. 3- 5 We were able to avoid 80% of these biopsies by using the ICON urine pregnancy test before the planned endometrial biopsy. Data by Carwright et al. 7 has shown that the urine specific gravity as an indicator of urine concentration may be an index by which one can avoid some of the false negative tests. He used an adjustment to the manufacturer's recommendation by increasing the urine volume tested when urine specific gravity was <1.015. This modification may be helpful in this group of patients as one can anticipate low levels of ~-hCG in the urine. SUMMARY
Endometrial biopsies for evaluation of the luteal phase should be taken within 2 days of the onset of menses. When these guidelines are followed and patients present at least 12 days after the thermogenic shift on BBT, the ICON pregnancy test is extremely rapid, sensitive, specific, and has predictive values close to 100%. If a biopsy is undertaken
164
Herbert et al.
Communications-in-brief
before this time there may be an increased risk of false negative results (i.e., a decreased sensitivity). The improved technology in urine pregnancy tests has now made it feasible to obtain accurate urine pregnancy tests before endometrial instrumentation with an increased level of confidence. It is recommended that this technology be used in the management of patients undergoing endometrial biopsies in the late luteal phase. Acknowledgement. We thank the Hybritech Corporation for providing the ICON kits for this investigation.
REFERENCES 1. Buxton CL, Olson LE: Endometrial biopsy inadvertently taken during conception cycle. Am J Obstet Gynecol 105: 702, 1969 2. Rosenfeld DL, Garcia C-R: Endometrial biopsy in the cycle of conception. Fertil Steril26:1088, 1975 3. Wentz AC: Endometrial biopsy in the evaluation of infertility. Fertil Steril33:121, 1980 4. Sulewski JM, Ward SP, McGaffic W: Endometrial biopsy during a cycle of conception. Fertil Steril 34:548, 1980 5. Wentz AC, Herbert CM III, Maxson WS, Hill GA, Pittaway DE: Cycle of conception endometrial biopsy. Fertil Steril 46:196, 1986 6. Chartier M, Roger M, Barrat J, Michelon B: Measurement of plasma human chorionic gonadotropin (hCG) and (3hCG activities in the late luteal phase: evidence of the occurrence of spontaneous menstrual abortions in infertile women. Fertil Steril31:134, 1979 7. Cartwright PS, Victory DF, Moore RA, Anderson JR, Brown DH: Performance of a new enzyme-linked immunoassay urine pregnancy test for the detection of ectopic gestation. Ann Emerg Med 15:1198, 1986
Fertility and Sterility
Vol. 53, No. 1, January 1990
Copyright© 1990 The American Fertility Society
Printed on acid-free paper in U.S.A.
Use of a sensitive urine pregnancy test before endometrial biopsies taken in the late luteal phase Carl M. Herbert, M.D.*t George A. Hill, M.D.* Wayne S. Maxson, M.D.:j:
Anne Colston Wentz, M.D.§ Kevin G. Osteen, Ph.D.*
Center for Fertility and Reproductive Research, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee
Endometrial biopsies taken during the late luteal phase are an important part of evaluating patients presenting with infertility, recurrent spontaneous abortion, and those undergoing ovulation induction. The late luteal phase endometrial biopsy should be taken 1 to 2 days before the onset of menses. An endometrial biopsy obtained during this time carries a theoretical risk of interrupting an early pregnancy that may have occurred during this cycle. Considering this risk many physicians have advised patients scheduled for an endometrial biopsy to either refrain from exposure or use barrier contraception during that cycle. These options, although effective, are not always well accepted or followed by patients anxious for every chance to conceive and already frustrated by multiple previous manipulations. In addition, the late luteal phase biopsy is interpreted according to the onset of the next menses. When contraception practices are not used and cycle of conception endometrial biopsies are obtained, they cannot be adequately evaluated. Several authors have examined the rate of spontaneous abortion subsequent to an endometrial biopsy during a cycle of conception Received June 12, 1989; revised and accepted September 5, 1989. * Department of Obstetrics and Gynecology, Vanderbilt U niversity Medical Center. · t Reprint requests: Carl M. Herbert, M.D. Center for Fertil· ity and Reproductive Research, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232·2515. :j: Present address: Northwest Center for Fertility and Repro· ductive Endocrinology, Margate, Florida. §Present address: Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois.
162
Herbert et al.
Communications-in-brief
and have not found an increase in miscarriage rates. 1- 5 Nevertheless, if a reliable, simple, rapid test could detect pregnancy in the late luteal phase before a biopsy, it would be advantageous for the patient. A urine pregnancy test using monoclonal technology in an enzyme linked immunoassay is available. Previous urine pregnancy tests have not been accurate for determining low levels of the beta subunit of human chorionic gonadotropin (~-hCG) in the urine during the very early weeks of pregnancy. False negative results from these less accurate tests have made them impractical for clinical evaluation before endometrial biopsies. Similarly, serum ~ hCG evaluations require at least several hours before results can be determined and, therefore, are not optimal for screening patients just before scheduled endometrial biopsies. These limitations have discouraged most physicians from obtaining a pregnancy test before endometrial biopsy.
MATERIALS AND METHODS
A prospective study was performed evaluating all patients presenting for luteal phase endometrial biopsies at the Cent~r for Fertility and Reproductive Research (C-FARR) at Vanderbilt University Medical Center. All patients were required to keep a basal body temperature (BBT) chart before their scheduled biopsy. All biopsies were scheduled to be performed within 2 days of the anticipated onset of menses, i.e., postovulatory day 12 or later. All patients were actively attempting pregnancy and were being treated for various conditions related to infertility. Fertility and Sterility
The monoclonal urine pregnancy test used was the ICON (Hybritech Corporation, San Diego, CA). We found this test to read positive when the serum levels of f1-hCG are in the range of 15 to 25 miU/mL (Second International Standard, 2nd IS). These values are consistent with serum levels achieved during the late luteal phase of a cycle of conception6 and, therefore, this test potentially offers a way of evaluating patients immediately before the endometrial biopsy. The following prospective study was designed to evaluate the efficacy of this form of urine pregnancy test in diagnosing pregnancies before the expected onset of menses and quantitating the serum level at which this test was positive. When patients presented to the clinic on their assigned day for endometrial biopsy, urine and blood specimens were obtained. These were taken to the gynecologic endocrinology laboratory where the urine pregnancy test was immediately performed. Urine pregnancy tests were performed in accordance with the instructions provided by the Hybritech Corporation and results were usually available in 5 to 10 minutes. However, the appearance of any blue coloration on the ICON disc was considered a positive result. Those patients who demonstrated a positive result did not undergo biopsy and the serum specimen was run that day in a radioimmunoassay (RIA) for a quantitative f1-hCG value (2nd IS) (Clinetics, Tustin, CA). Serum specimens from patients with negative urine tests were batch run by RiA at the end of the study or before if a question arose about false negative urine tests. Pregnant patients were followed for the outcomes of their pregnancies. RESULTS
One hundred twenty-four consecutive patients presented for endometrial biopsy over a 6 month period. Of these 124 patients, 11 (8.9%) were ultimately determined to be pregnant at the time they presented for biopsy. Two of the 11 (18%) patients had negative urine ICON tests before their biopsy and, therefore, underwent an endometrial biopsy, but were subsequently found. to be pregnant. These two patients successfully carried their pregnancies to term. Nine of the 11 patients pregnant at the time they presented for their endometrial biopsy were detected by the urine ICON and avoided an endometrial biopsy. All sera from the 113 patients demonstrating a negative urine ICON and normal menses were negative for f1-hCG by RIA. From Vol. 53, No.1, January 1990
Table 1 Day After Thermogenic Shift on BBT and Serum ,8-hCG Value for Each Patient Who Was Pregnant at the Time of Their Planned Endometrial Biopsy
Patient
Days after thermogenic shift
Urine ICON
Serum ,8-hCG miU/mL•
1 2 3 4 5 6
13 13
7
12 12 13
8 9 10 11
+ + + + + + + + +
b
12 12 11
29 40 79 236' 25 9 19 35 28
11 10
22 4.8
"Second IS. b No BBT available. ' Twin gestation.
these data the sensitivity and specificity of this test are 82% and 100%, respectively. The positive predictive value is 100%, and the negative predictive value is 98%. The serum f1-hCG value present in each of these patients is shown in Table 1. Evaluation of the false negative urine ICON results showed one patient with a very low serum f1-hCG value that would be expected to produce a negative result by the standard interpretation of the ICON. On review of the patient's BBT chart, it was determined that she presented only 10 days after the thermogenic shift and was, therefore, felt to have been missed on the basis of being too early in the gestation of her pregnancy. The other patient presented 11 days after the thermogenic shift on her BBT chart but did have a quantitative amount of f1-hCG in the serum that produced a positive ICON in several of the other patients. All pregnant patients who were at least 12 days after thermogenic shift on BBT were diagnosed as positive by the urine pregnancy test. DISCUSSION
The monoclonal technology in conjunction with enzyme linkage has provided new sensitivity to urine pregnancy testing. Employing this technology before endometrial biopsies has proven efficacious in this study by decreasing the incidence of a cycle of conception endometrial biopsy from a possible 8.9% to an actual 1.6%. The urine ICON was interpreted as positive when serum levels were Herbert et al.
Communications-in-brief
163
as low as 9.2 miU/mL (2nd IS) in the serum. This sensitivity will allow physicians to avoid many unnecessary biopsies. The endometrial biopsy taken during a cycle of conception cannot be adequately interpreted and, therefore, is of no benefit to the patient. In addition, a biopsy in the cycle of conception may create some increased risk of disruption of the pregnancy. The rate of patients being pregnant when they present for an endometrial biopsy was 11 of 124 (8.9%) that is consistent with the findings of other studies in the literature. 3- 5 We were able to avoid 80% of these biopsies by using the ICON urine pregnancy test before the planned endometrial biopsy. Data by Carwright et al. 7 has shown that the urine specific gravity as an indicator of urine concentration may be an index by which one can avoid some of the false negative tests. He used an adjustment to the manufacturer's recommendation by increasing the urine volume tested when urine specific gravity was <1.015. This modification may be helpful in this group of patients as one can anticipate low levels of ~-hCG in the urine. SUMMARY
Endometrial biopsies for evaluation of the luteal phase should be taken within 2 days of the onset of menses. When these guidelines are followed and patients present at least 12 days after the thermogenic shift on BBT, the ICON pregnancy test is extremely rapid, sensitive, specific, and has predictive values close to 100%. If a biopsy is undertaken
164
Herbert et al.
Communications-in-brief
before this time there may be an increased risk of false negative results (i.e., a decreased sensitivity). The improved technology in urine pregnancy tests has now made it feasible to obtain accurate urine pregnancy tests before endometrial instrumentation with an increased level of confidence. It is recommended that this technology be used in the management of patients undergoing endometrial biopsies in the late luteal phase. Acknowledgement. We thank the Hybritech Corporation for providing the ICON kits for this investigation.
REFERENCES 1. Buxton CL, Olson LE: Endometrial biopsy inadvertently taken during conception cycle. Am J Obstet Gynecol 105: 702, 1969 2. Rosenfeld DL, Garcia C-R: Endometrial biopsy in the cycle of conception. Fertil Steril26:1088, 1975 3. Wentz AC: Endometrial biopsy in the evaluation of infertility. Fertil Steril33:121, 1980 4. Sulewski JM, Ward SP, McGaffic W: Endometrial biopsy during a cycle of conception. Fertil Steril 34:548, 1980 5. Wentz AC, Herbert CM III, Maxson WS, Hill GA, Pittaway DE: Cycle of conception endometrial biopsy. Fertil Steril 46:196, 1986 6. Chartier M, Roger M, Barrat J, Michelon B: Measurement of plasma human chorionic gonadotropin (hCG) and (3hCG activities in the late luteal phase: evidence of the occurrence of spontaneous menstrual abortions in infertile women. Fertil Steril31:134, 1979 7. Cartwright PS, Victory DF, Moore RA, Anderson JR, Brown DH: Performance of a new enzyme-linked immunoassay urine pregnancy test for the detection of ectopic gestation. Ann Emerg Med 15:1198, 1986
Fertility and Sterility