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Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic
Letters to the Editors As other authors have observed, we agree that the concept that cervical intraepithelial neoplasia (CIN) 2 and 3 lesions are high grade, requiring treatment, and CIN 1 does not is an oversimplification of biological reality.1 When managing patients on the basis of a colposcopic biopsy, it must be remembered that this biopsy may not be representative of the worst abnormality, that lesions may progress or regress over time, and that the reporting of CIN grade is subject to significant interobserver and intraobserver variability. Thus, while the majority of lesions reported as CIN 2 on colposcopic biopsy have a low risk of progression to or being associated with invasive cancer, some will. Therefore, the grouping of CIN 2 with CIN 1 for the purpose of management may be equally misleading. The safety of conservative management of biopsy-proven CIN 2 in women ⬍25 years of age is underpinned by the rarity of cancer when compared with the frequency of the diagnosis of CIN 2 in this age group. This inevitably asks the question as to whether it is wise to screen this age group at all. Although the argument against screening is compelling,2 we continue to encounter screen-detected microinvasive cancers in young women and we are all familiar with the disastrous effects of invasive cancer in such patients. In screening programs in which young women continue to be screened, an emphasis should be placed on minimization of harm. The key to this management conundrum probably lies in the identification of biomarkers that will more accurately reflect
www.AJOG.org the biology of disease. As suggested by our colleagues, further research in this field is important. f Peter H. Sykes, MBChB Obstetrics and Gynecology University of Otago, Christchurch 5/2 Riccarton Ave. Christchurch, Canterbury, 8011 New Zealand [email protected] Bree McAllum, MBChB Bryony Simcock, MBChB University of Otago, Christchurch Christchurch, Canterbury, New Zealand Lynn Sadler, MD Aukland District Health Board The authors report no conflict of interest.
REFERENCES 1. Syrjanen K, Kataja V, Yliskoski M, Chang F, Syrjanen S, Saarikoski S. Natural history of cervical human papillomavirus lesions does not substantiate the biologic relevance of the Bethesda system. Obstet Gynecol 1992;79:675-82. 2. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population-based case-control study of prospectively recorded data. BMJ 2009;339:2968. © 2012 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.11.004
Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic TO THE EDITORS: In a recent issue of American Journal of Obstetrics and Gynecology, Nurmohamed et al1 conclude that methotrexate administered to patients misdiagnosed with ectopic pregnancy may cause severe fetal malformations or demise, and imply in their discussion that ultrasound performed by emergency physicians with limited training contributed to misdiagnosis. We agree that such errors are catastrophic; however, we find it extremely unlikely that point-of-care emergency ultrasound has contributed to these errors. The source of data for this study was the teratogen information service, which does not have access to patient records. Therefore, while the authors may be able to determine that half of their cases were diagnosed in the emergency department, they are unable to determine who performed the imaging study or how the decision to administer methotrexate was made. We would be shocked if the emergency physicians performed these ultrasound examinations and then unilaterally proceeded to give methotrexate without obstetric consultation at a minimum. The American College of Emergency Physicians policy statement clearly states that the goal for focused emergency ultrasound is to identify intrauterine pregnancy.2 In patients not utilizing assisted reproductivetechnologies,thishasbeenshowntoexcludeectopicpregnancy with a negative predictive value of essentially 100%.3 “Intrae12
American Journal of Obstetrics & Gynecology MARCH 2012
uterine pregnancy” is thus listed as a core application, not the diagnosis of ectopic pregnancy.2 Thus, while the diagnosis of an intrauterine pregnancy is reassuring that the patient does not have an ectopic, failure to identify an intrauterine pregnancy on point-of-care ultrasoundwouldpromptmostemergencyphysicianstoobtainconsultative imaging and recommendations, as stated in well-established algorithms in the literature.4 In most centers, there is a process for case and imaging review among the obstetrician, emergency physician, and/or radiologist prior to methotrexate administration. The article refers to the “relative ease of methotrexate administration.” If this is the case, at any institution, then there are inherent process issues that must be addressed. In addition, the indications for methotrexate are clear. We would be very curious to know what the findings were on these ultrasound examinations that led the caregivers to proceed with medical termination and who ultimately decided to give the medication. As noted in the article, emergency physician–performed pelvic ultrasound has been shown to be a safe and effective method to evaluate first-trimester symptoms,5 and it is often difficult to obtain timely ultrasound studies through the radiology department at many institutions. All clinicians, community emergency department physicians or otherwise, should only perform those procedures where they have been appropriately trained and have the adequate skill set. While we
Letters to the Editors
www.AJOG.org agree that caution in the diagnosis of ectopic pregnancy and the administration of methotrexate is essential, this study should not be used to question the safety or effectiveness of properly utilized pointof-care emergency physician–performed ultrasound in the hands of well-trained and experienced users. f Christopher Raio, MD, RDMS Adam Ash, DO, RDMS William Beaumont Army Medical Center 5005 N. Piedras St. El Paso, TX 79920 [email protected] Mathew Nelson, DO, RDMS Robert Bramante, MD, RDMS North Shore University Hospital Christopher Moore, MD, RDMS Yale University The authors report no conflict of interest.
REFERENCES 1. Nurmohamed L, Moretti ME, Schechter T, et al. Outcomes following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;205:533.e1-3. 2. American College of Emergency Physicians Board of Directors. Policy statement: emergency ultrasound guidelines. Ann Emerg Med 2009; 53:550-70. 3. Mateer JR, Valley VT, Aiman EJ, et al. Outcome analysis of a protocol including bedside endovaginal sonography in patients at risk for ectopic pregnancy. Ann Emerg Med 1996;27:283-9. 4. Moore CL, Promes SB. Ultrasound in pregnancy. Emerg Med Clin North Am 2004;22:697-722. 5. Stein JC. Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. Ann Emerg Med 2010; 56:674-83. Published by Mosby, Inc. doi: 10.1016/j.ajog.2011.11.013
REPLY We thank Raio and colleagues1 for their interest in our work. We reported that preventable fetal deaths or severe malformations in otherwise healthy pregnancies occurred by administering the teratogen methotrexate to early misdiagnosed intrauterine pregnancies,2 a phenomenon that has been largely overlooked in the medical literature. By focusing on identifying the physician discipline responsible for those diagnostic errors, Raio and colleagues1 detract from the disquieting findings described in our work. Indeed, the aim of the study was not to point fingers or blame any particular clinician group. Our findings clearly show that diagnostic ultrasound errors were not restricted, nor dominated, by any subspecialty group. We found it challenging to follow the rationale of Raio and colleagues1 for the concerns raised. It is inconsistent to claim that it is “extremely unlikely that point-of-care emergency ultrasound has contributed to these errors,” while admitting that diagnosis of ectopic is not a core application of focused emergency ultrasound and that it is “often difficult to obtain timely ultrasound studies through the radiology department at many
institutions.” In fact, obstetrical consultation is not always available at all emergency departments, particularly in remote or rural areas, and real-time decisions may need to be made by the emergency physician. Raio and colleagues1 also suggest that focused emergency ultrasound has a 100% negative predictive value, based on an article by Mateer et al.3 A high negative predictive value means that such ultrasounds would virtually never misclassify an ectopic pregnancy as an intrauterine pregnancy. However, this value does not speak to the frequency with which an intrauterine pregnancy would be misclassified as ectopic, which is the clinical scenario we were describing. Moreover, this article was misquoted. In fact, Mateer et al3 concluded that the addition of bedside endovaginal ultrasound, performed by well-trained emergency physicians, to their diagnosis protocol did not statistically lower the overall rate of missed ectopic pregnancies. This article clearly strengthens our message that diagnostic errors regarding pregnancy location in early stages can occur in the hands of well-trained, experienced physicians. The statement of Raio and colleagues1 about “the relative ease of methotrexate administration” was also taken out of context. Within our article, “ease” was juxtaposed against the alternative management option, which is surgical termination. Finally, it would be naïve to assume that even well-established and strictly followed clinical guidelines and algorithms can be applied in every single case and are error-proof in all complex circumstances. As teratology information specialists, our role is to raise awareness of serious fetal risks. We are pleased that this work has stimulated discussion about the complexities surrounding the diagnosis and management of these cases, and look forward f to improvements that will diminish their recurrence. Myla E. Moretti, MSc Gideon Koren, MD Motherisk Program, Division of Clinical Pharmacology and Toxicology Yaron Finkelstein, MD Motherisk Program, Divisions of Clinical Pharmacology and Toxicology and Emergency Medicine Hospital for Sick Children, University of Toronto 555 University Ave. Toronto, Ontario, Canada M5G 1X8 [email protected] The authors report no conflict of interest.
REFERENCES 1. Raio C, Ash A, Nelson M, Bramante R, Moore C. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;206:eX. 2. Nurmohamed L, Moretti ME, Schechter T, et al. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;205:533.e1-3. 3. Mateer JR, Valley VT, Aiman EJ, Phelan MB, Thoma ME, Kefer MP. Outcome analysis of a protocol including bedside endovaginal sonography in patients at risk for ectopic pregnancy. Ann Emerg Med 1996; 27:283-9. © 2012 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.11.014
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www.AJOG.org the biology of disease. As suggested by our colleagues, further research in this field is important. f Peter H. Sykes, MBChB Obstetrics and Gynecology University of Otago, Christchurch 5/2 Riccarton Ave. Christchurch, Canterbury, 8011 New Zealand [email protected] Bree McAllum, MBChB Bryony Simcock, MBChB University of Otago, Christchurch Christchurch, Canterbury, New Zealand Lynn Sadler, MD Aukland District Health Board The authors report no conflict of interest.
REFERENCES 1. Syrjanen K, Kataja V, Yliskoski M, Chang F, Syrjanen S, Saarikoski S. Natural history of cervical human papillomavirus lesions does not substantiate the biologic relevance of the Bethesda system. Obstet Gynecol 1992;79:675-82. 2. Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: population-based case-control study of prospectively recorded data. BMJ 2009;339:2968. © 2012 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.11.004
Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic TO THE EDITORS: In a recent issue of American Journal of Obstetrics and Gynecology, Nurmohamed et al1 conclude that methotrexate administered to patients misdiagnosed with ectopic pregnancy may cause severe fetal malformations or demise, and imply in their discussion that ultrasound performed by emergency physicians with limited training contributed to misdiagnosis. We agree that such errors are catastrophic; however, we find it extremely unlikely that point-of-care emergency ultrasound has contributed to these errors. The source of data for this study was the teratogen information service, which does not have access to patient records. Therefore, while the authors may be able to determine that half of their cases were diagnosed in the emergency department, they are unable to determine who performed the imaging study or how the decision to administer methotrexate was made. We would be shocked if the emergency physicians performed these ultrasound examinations and then unilaterally proceeded to give methotrexate without obstetric consultation at a minimum. The American College of Emergency Physicians policy statement clearly states that the goal for focused emergency ultrasound is to identify intrauterine pregnancy.2 In patients not utilizing assisted reproductivetechnologies,thishasbeenshowntoexcludeectopicpregnancy with a negative predictive value of essentially 100%.3 “Intrae12
American Journal of Obstetrics & Gynecology MARCH 2012
uterine pregnancy” is thus listed as a core application, not the diagnosis of ectopic pregnancy.2 Thus, while the diagnosis of an intrauterine pregnancy is reassuring that the patient does not have an ectopic, failure to identify an intrauterine pregnancy on point-of-care ultrasoundwouldpromptmostemergencyphysicianstoobtainconsultative imaging and recommendations, as stated in well-established algorithms in the literature.4 In most centers, there is a process for case and imaging review among the obstetrician, emergency physician, and/or radiologist prior to methotrexate administration. The article refers to the “relative ease of methotrexate administration.” If this is the case, at any institution, then there are inherent process issues that must be addressed. In addition, the indications for methotrexate are clear. We would be very curious to know what the findings were on these ultrasound examinations that led the caregivers to proceed with medical termination and who ultimately decided to give the medication. As noted in the article, emergency physician–performed pelvic ultrasound has been shown to be a safe and effective method to evaluate first-trimester symptoms,5 and it is often difficult to obtain timely ultrasound studies through the radiology department at many institutions. All clinicians, community emergency department physicians or otherwise, should only perform those procedures where they have been appropriately trained and have the adequate skill set. While we
Letters to the Editors
www.AJOG.org agree that caution in the diagnosis of ectopic pregnancy and the administration of methotrexate is essential, this study should not be used to question the safety or effectiveness of properly utilized pointof-care emergency physician–performed ultrasound in the hands of well-trained and experienced users. f Christopher Raio, MD, RDMS Adam Ash, DO, RDMS William Beaumont Army Medical Center 5005 N. Piedras St. El Paso, TX 79920 [email protected] Mathew Nelson, DO, RDMS Robert Bramante, MD, RDMS North Shore University Hospital Christopher Moore, MD, RDMS Yale University The authors report no conflict of interest.
REFERENCES 1. Nurmohamed L, Moretti ME, Schechter T, et al. Outcomes following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;205:533.e1-3. 2. American College of Emergency Physicians Board of Directors. Policy statement: emergency ultrasound guidelines. Ann Emerg Med 2009; 53:550-70. 3. Mateer JR, Valley VT, Aiman EJ, et al. Outcome analysis of a protocol including bedside endovaginal sonography in patients at risk for ectopic pregnancy. Ann Emerg Med 1996;27:283-9. 4. Moore CL, Promes SB. Ultrasound in pregnancy. Emerg Med Clin North Am 2004;22:697-722. 5. Stein JC. Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. Ann Emerg Med 2010; 56:674-83. Published by Mosby, Inc. doi: 10.1016/j.ajog.2011.11.013
REPLY We thank Raio and colleagues1 for their interest in our work. We reported that preventable fetal deaths or severe malformations in otherwise healthy pregnancies occurred by administering the teratogen methotrexate to early misdiagnosed intrauterine pregnancies,2 a phenomenon that has been largely overlooked in the medical literature. By focusing on identifying the physician discipline responsible for those diagnostic errors, Raio and colleagues1 detract from the disquieting findings described in our work. Indeed, the aim of the study was not to point fingers or blame any particular clinician group. Our findings clearly show that diagnostic ultrasound errors were not restricted, nor dominated, by any subspecialty group. We found it challenging to follow the rationale of Raio and colleagues1 for the concerns raised. It is inconsistent to claim that it is “extremely unlikely that point-of-care emergency ultrasound has contributed to these errors,” while admitting that diagnosis of ectopic is not a core application of focused emergency ultrasound and that it is “often difficult to obtain timely ultrasound studies through the radiology department at many
institutions.” In fact, obstetrical consultation is not always available at all emergency departments, particularly in remote or rural areas, and real-time decisions may need to be made by the emergency physician. Raio and colleagues1 also suggest that focused emergency ultrasound has a 100% negative predictive value, based on an article by Mateer et al.3 A high negative predictive value means that such ultrasounds would virtually never misclassify an ectopic pregnancy as an intrauterine pregnancy. However, this value does not speak to the frequency with which an intrauterine pregnancy would be misclassified as ectopic, which is the clinical scenario we were describing. Moreover, this article was misquoted. In fact, Mateer et al3 concluded that the addition of bedside endovaginal ultrasound, performed by well-trained emergency physicians, to their diagnosis protocol did not statistically lower the overall rate of missed ectopic pregnancies. This article clearly strengthens our message that diagnostic errors regarding pregnancy location in early stages can occur in the hands of well-trained, experienced physicians. The statement of Raio and colleagues1 about “the relative ease of methotrexate administration” was also taken out of context. Within our article, “ease” was juxtaposed against the alternative management option, which is surgical termination. Finally, it would be naïve to assume that even well-established and strictly followed clinical guidelines and algorithms can be applied in every single case and are error-proof in all complex circumstances. As teratology information specialists, our role is to raise awareness of serious fetal risks. We are pleased that this work has stimulated discussion about the complexities surrounding the diagnosis and management of these cases, and look forward f to improvements that will diminish their recurrence. Myla E. Moretti, MSc Gideon Koren, MD Motherisk Program, Division of Clinical Pharmacology and Toxicology Yaron Finkelstein, MD Motherisk Program, Divisions of Clinical Pharmacology and Toxicology and Emergency Medicine Hospital for Sick Children, University of Toronto 555 University Ave. Toronto, Ontario, Canada M5G 1X8 [email protected] The authors report no conflict of interest.
REFERENCES 1. Raio C, Ash A, Nelson M, Bramante R, Moore C. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;206:eX. 2. Nurmohamed L, Moretti ME, Schechter T, et al. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol 2011;205:533.e1-3. 3. Mateer JR, Valley VT, Aiman EJ, Phelan MB, Thoma ME, Kefer MP. Outcome analysis of a protocol including bedside endovaginal sonography in patients at risk for ectopic pregnancy. Ann Emerg Med 1996; 27:283-9. © 2012 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.11.014
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