- Email: [email protected]
Endometrial biopsy should be abandoned as a routine component of the infertility evaluation
FERTILITY AND STERILITY威 VOL. 82, NO. 5, NOVEMBER 2004 Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Endometrial biopsy should be abandoned as a routine component of the infertility evaluation Ralph R. Kazer, M.D. Feinberg School of Medicine of Northwestern University, Chicago, Illinois
Endometrial biopsies are of little value in the evaluation of infertile couples. Their usefulness in the evaluation of couples with repeated early pregnancy loss remains to be demonstrated. (Fertil Steril威 2004;82:1297– 8. ©2004 by American Society for Reproductive Medicine.)
Prevailing views regarding the proper components of an infertility evaluation constantly undergo reevaluation and revision. Practice patterns inevitably change in the face of technical advances and newly acquired data derived from clinical studies. With respect to the latter, the quality and sophistication of clinical research dealing with infertility have been steadily improving in recent years. Welldesigned studies are now shedding new light on the efficacy and cost efficiency of longstanding diagnostic and therapeutic practices. Multicenter studies, in particular, are uniquely suited to address clinical questions requiring the enrollment of large numbers of subjects.
Received May 20, 2004; revised and accepted May 20, 2004. Reprint requests: Ralph R. Kazer, M.D., Feinberg School of Medicine of Northwestern University, 680 North Lake Shore Drive, Suite 1015, Chicago, Illinois 60611 (FAX: 312926-6643; E-mail: rkazer@ northwestern.edu). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 05.080
In this issue of Fertility and Sterility, three articles describe the results of a large multicenter trial designed in 1998 to evaluate the usefulness of the endometrial biopsy (EMB) in the evaluation of the infertile couple (1–3). The main article (1) convincingly demonstrates that infertile couples do not have an increased prevalence of out-of-phase biopsies in either the midluteal or late luteal phase when compared to fertile controls. Furthermore, the overall incidence of out-of-phase biopsies in both groups was remarkably high. Together, these findings render the potential usefulness of EMB as a screening test in a routine infertility evaluation quite low. The first companion article (2) describes the extent of observer variability in endometrial dating. Although this issue has been explored previously, the large number of subjects studied in conjunction with careful statistical analysis lends unusual strength to the
conclusion of these articles that even small variations in dating may lead to frequent changes in the characterization of biopsies as in-phase or out-of-phase. The second companion article (3) reports that both fertile and infertile women have positive LH surge determinations which are followed by biopsies revealing proliferative endometrium about 7% of the time. This suggests that women who have regular menses and positive home ovulation determinations may nevertheless, on the average, fail to ovulate normally roughly once a year. The authors of these articles are all experienced clinical investigators, and the high quality of their experimental design as well as the degree of sophistication used in the subsequent statistical analyses reflect this. One modest concern may nevertheless bear some scrutiny. Results from the main article reveal, if anything, a higher rate of out-of-phase biopsies in the fertile controls when compared to the infertile group. This raises the question as to whether the inclusion or exclusion criteria for the two groups could somehow have introduced a selection bias that could be reflected by this unexpected finding. The investigators specifically addressed one possibility, the potential impact of recent oral contraceptive use, and persuasively argued against its possible relevance. One other possibility should be addressed. The fertile controls all had a delivery less than 24 months before the time of their biopsies. Presumably, a substantial fraction of them breast-fed their babies. Although an interval of 2 months without breast-feeding was 1297
mandated before biopsy, even a modest carryover effect might impact the overall number of out-of-phase biopsies in the fertile group. Although it might be unlikely that such an effect could be important, it would be reassuring if it could be demonstrated that the subjects who breast-fed relatively close to their biopsies were not more likely to have out-ofphase biopsies, or at the very least, were small in number. Taken together, the findings of these articles have important implications for practitioners. In the first place, it is no longer possible to justify the performance of EMB as a routine screening test in the basic infertility evaluation. One would have thought that this was not a particularly common practice, but the investigators provide data indicating that in roughly 25% of infertility evaluations, the female partner still undergoes EMB. In particular circumstances in which various types of endometrial pathology are of concern, the EMB will, of course, remain a useful tool. Second, the observation of a positive LH surge should not be viewed by itself as adequate documentation of ovulation. Basal body temperature (BBT) charting or midluteal serum P determinations should still be viewed as both reliable and adequate, and EMB is unnecessary. This is not the first time a commonly used element of the infertility evaluation has been found to be of little or no value. For example, the routine screening of ovulatory infertile patients for subclinical hypothyroidism has also been demonstrated to be unwarranted (4). It is likely that views on the proper evaluation of the infertile couple will continue to evolve, and new modalities will undoubtedly be incorporated into standard workups. Accumulating experience in the care of patients undergoing therapy with IVF reveals that many couples who previously had been categorized as having unexplained infertility are ultimately found to have an ovarian reserve problem. It is not hard to foresee a time in the near future where the routine endocrine component of the infertility evaluation is limited to documentation of ovulation and some assessment of ovarian reserve. The hypothesis of these investigators that more sophisticated tests of luteal phase adequacy may ultimately prove clinically useful remains to be tested. Parenthetically, the usefulness and cost effectiveness of routine laparoscopy in the assessment of the asymptomatic infertility patient comprises another particularly appropriate subject for proper study, given its frequency and high cost.
1298 Kazer
Lack of utility of endometrial biopsy
It is also worthwhile to explore the implications of these findings for current diagnostic practices directed toward the patient with recurrent pregnancy wastage. The main article approaches this issue in a very circumspect way, but argues convincingly that, even if luteal phase deficiency (LPD) exists as an important clinical problem, the EMB cannot be used to identify or assess it. Given that this disorder has historically been defined in terms of EMB results, their findings lead to the inescapable conclusion that, as a practical matter, it is impossible to make the diagnosis of LPD using currently available technology. Naturally, the patient with a persistently short luteal phase can be identified without an EMB, but this is not a common clinical problem. The question of whether LPD even exists as a significant clinical problem in patients with recurrent pregnancy wastage remains, remarkably, an open question after decades of study. In no other clinical arena would studies of the quality seen in these articles be more welcome. Patients with repeated early losses are among the most desperate of those we care for, and consequently are particularly vulnerable to exploitation in the form of tests and treatments of unproven value. In conclusion, the investigators should be congratulated on the contribution they have made with this enormous effort. As continuing scrutiny is brought to bear on the usefulness of commonly used diagnostic and therapeutic approaches, we can anticipate a time when all of what we propose to our patients can be justified with good science. To the extent that we accomplish this, particularly if this winnowing process results in significantly decreased costs, it will be much easier for us as practitioners to not only spare our patients potentially wasteful, painful, expensive, and time-consuming procedures, but to successfully lobby for the ultimate inclusion of infertility evaluation and therapy as standard components in all health insurance plans. References 1. Coutifaris C, Myers ER, Guzick DS, Diamond MP, Carson SA, Legro RS, et al., for the NICHD National Cooperative Reproductive Medicine Network. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004;82:1264 –72. 2. Myers ER, Silva S, Barnhart K, Groben PA, Richardson MS, Robboy SJ, et al., for the NICHD National Cooperative Reproductive Medicine Network. Interobserver and intraobserver variability in the histological dating of the endometrium in fertile and infertile women. Fertil Steril 2004;82:1278 – 82. 3. McGovern PG, Meyers ER, Silva S, Coutifaris C, Carson SA, Legro RS, et al., for the NICHD National Cooperative Reproductive Medicine Network. Absence of secretory endometrium after false-positive home urine luteinizing hormone testing. Fertil Steril 2004;82:1273–7. 4. Lincoln SR, Ke RW, Kutteh WH. Screening for hypothyroidism in infertile women. J Repro Med 1999;44:455–7.
Vol. 82, No. 5, November 2004
Endometrial biopsy should be abandoned as a routine component of the infertility evaluation Ralph R. Kazer, M.D. Feinberg School of Medicine of Northwestern University, Chicago, Illinois
Endometrial biopsies are of little value in the evaluation of infertile couples. Their usefulness in the evaluation of couples with repeated early pregnancy loss remains to be demonstrated. (Fertil Steril威 2004;82:1297– 8. ©2004 by American Society for Reproductive Medicine.)
Prevailing views regarding the proper components of an infertility evaluation constantly undergo reevaluation and revision. Practice patterns inevitably change in the face of technical advances and newly acquired data derived from clinical studies. With respect to the latter, the quality and sophistication of clinical research dealing with infertility have been steadily improving in recent years. Welldesigned studies are now shedding new light on the efficacy and cost efficiency of longstanding diagnostic and therapeutic practices. Multicenter studies, in particular, are uniquely suited to address clinical questions requiring the enrollment of large numbers of subjects.
Received May 20, 2004; revised and accepted May 20, 2004. Reprint requests: Ralph R. Kazer, M.D., Feinberg School of Medicine of Northwestern University, 680 North Lake Shore Drive, Suite 1015, Chicago, Illinois 60611 (FAX: 312926-6643; E-mail: rkazer@ northwestern.edu). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 05.080
In this issue of Fertility and Sterility, three articles describe the results of a large multicenter trial designed in 1998 to evaluate the usefulness of the endometrial biopsy (EMB) in the evaluation of the infertile couple (1–3). The main article (1) convincingly demonstrates that infertile couples do not have an increased prevalence of out-of-phase biopsies in either the midluteal or late luteal phase when compared to fertile controls. Furthermore, the overall incidence of out-of-phase biopsies in both groups was remarkably high. Together, these findings render the potential usefulness of EMB as a screening test in a routine infertility evaluation quite low. The first companion article (2) describes the extent of observer variability in endometrial dating. Although this issue has been explored previously, the large number of subjects studied in conjunction with careful statistical analysis lends unusual strength to the
conclusion of these articles that even small variations in dating may lead to frequent changes in the characterization of biopsies as in-phase or out-of-phase. The second companion article (3) reports that both fertile and infertile women have positive LH surge determinations which are followed by biopsies revealing proliferative endometrium about 7% of the time. This suggests that women who have regular menses and positive home ovulation determinations may nevertheless, on the average, fail to ovulate normally roughly once a year. The authors of these articles are all experienced clinical investigators, and the high quality of their experimental design as well as the degree of sophistication used in the subsequent statistical analyses reflect this. One modest concern may nevertheless bear some scrutiny. Results from the main article reveal, if anything, a higher rate of out-of-phase biopsies in the fertile controls when compared to the infertile group. This raises the question as to whether the inclusion or exclusion criteria for the two groups could somehow have introduced a selection bias that could be reflected by this unexpected finding. The investigators specifically addressed one possibility, the potential impact of recent oral contraceptive use, and persuasively argued against its possible relevance. One other possibility should be addressed. The fertile controls all had a delivery less than 24 months before the time of their biopsies. Presumably, a substantial fraction of them breast-fed their babies. Although an interval of 2 months without breast-feeding was 1297
mandated before biopsy, even a modest carryover effect might impact the overall number of out-of-phase biopsies in the fertile group. Although it might be unlikely that such an effect could be important, it would be reassuring if it could be demonstrated that the subjects who breast-fed relatively close to their biopsies were not more likely to have out-ofphase biopsies, or at the very least, were small in number. Taken together, the findings of these articles have important implications for practitioners. In the first place, it is no longer possible to justify the performance of EMB as a routine screening test in the basic infertility evaluation. One would have thought that this was not a particularly common practice, but the investigators provide data indicating that in roughly 25% of infertility evaluations, the female partner still undergoes EMB. In particular circumstances in which various types of endometrial pathology are of concern, the EMB will, of course, remain a useful tool. Second, the observation of a positive LH surge should not be viewed by itself as adequate documentation of ovulation. Basal body temperature (BBT) charting or midluteal serum P determinations should still be viewed as both reliable and adequate, and EMB is unnecessary. This is not the first time a commonly used element of the infertility evaluation has been found to be of little or no value. For example, the routine screening of ovulatory infertile patients for subclinical hypothyroidism has also been demonstrated to be unwarranted (4). It is likely that views on the proper evaluation of the infertile couple will continue to evolve, and new modalities will undoubtedly be incorporated into standard workups. Accumulating experience in the care of patients undergoing therapy with IVF reveals that many couples who previously had been categorized as having unexplained infertility are ultimately found to have an ovarian reserve problem. It is not hard to foresee a time in the near future where the routine endocrine component of the infertility evaluation is limited to documentation of ovulation and some assessment of ovarian reserve. The hypothesis of these investigators that more sophisticated tests of luteal phase adequacy may ultimately prove clinically useful remains to be tested. Parenthetically, the usefulness and cost effectiveness of routine laparoscopy in the assessment of the asymptomatic infertility patient comprises another particularly appropriate subject for proper study, given its frequency and high cost.
1298 Kazer
Lack of utility of endometrial biopsy
It is also worthwhile to explore the implications of these findings for current diagnostic practices directed toward the patient with recurrent pregnancy wastage. The main article approaches this issue in a very circumspect way, but argues convincingly that, even if luteal phase deficiency (LPD) exists as an important clinical problem, the EMB cannot be used to identify or assess it. Given that this disorder has historically been defined in terms of EMB results, their findings lead to the inescapable conclusion that, as a practical matter, it is impossible to make the diagnosis of LPD using currently available technology. Naturally, the patient with a persistently short luteal phase can be identified without an EMB, but this is not a common clinical problem. The question of whether LPD even exists as a significant clinical problem in patients with recurrent pregnancy wastage remains, remarkably, an open question after decades of study. In no other clinical arena would studies of the quality seen in these articles be more welcome. Patients with repeated early losses are among the most desperate of those we care for, and consequently are particularly vulnerable to exploitation in the form of tests and treatments of unproven value. In conclusion, the investigators should be congratulated on the contribution they have made with this enormous effort. As continuing scrutiny is brought to bear on the usefulness of commonly used diagnostic and therapeutic approaches, we can anticipate a time when all of what we propose to our patients can be justified with good science. To the extent that we accomplish this, particularly if this winnowing process results in significantly decreased costs, it will be much easier for us as practitioners to not only spare our patients potentially wasteful, painful, expensive, and time-consuming procedures, but to successfully lobby for the ultimate inclusion of infertility evaluation and therapy as standard components in all health insurance plans. References 1. Coutifaris C, Myers ER, Guzick DS, Diamond MP, Carson SA, Legro RS, et al., for the NICHD National Cooperative Reproductive Medicine Network. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004;82:1264 –72. 2. Myers ER, Silva S, Barnhart K, Groben PA, Richardson MS, Robboy SJ, et al., for the NICHD National Cooperative Reproductive Medicine Network. Interobserver and intraobserver variability in the histological dating of the endometrium in fertile and infertile women. Fertil Steril 2004;82:1278 – 82. 3. McGovern PG, Meyers ER, Silva S, Coutifaris C, Carson SA, Legro RS, et al., for the NICHD National Cooperative Reproductive Medicine Network. Absence of secretory endometrium after false-positive home urine luteinizing hormone testing. Fertil Steril 2004;82:1273–7. 4. Lincoln SR, Ke RW, Kutteh WH. Screening for hypothyroidism in infertile women. J Repro Med 1999;44:455–7.
Vol. 82, No. 5, November 2004