To the Editor:
We welcome the recently published article by the Practice Committee of the American Society for Reproductive Medicine on the medical treatment of ectopic pregnancy (EP) (1). In selected patients, Methotrexate (MTX) is an effective treatment for unruptured EP and helps to avoid surgical intervention.
We are however concerned about some aspects of the committee’s opinion. The document advocates the use of single measurements of serum human chorionic gonadotropin (hCG) as a discriminatory zone to separate abnormal from normal gestations at the first presentation, if a transvaginal ultrasound scan (TVS) fails to identify the location of a pregnancy. This approach is not without risk. For example, it does not take into account the possibility of a multiple pregnancy where for a given gestational age serum hCG levels are higher than in a singleton. Consequently, hCG levels in multiple pregnancies are usually much higher before the pregnancy reaches a size that may be visualized on TVS (2). This could result in the administration of MTX to a woman with a pregnancy of unknown location (PUL) who has a developing twin pregnancy rather than an underlying EP. Such an outcome would in all likelihood lead to major congenital abnormalities in the developing fetuses. We recommend that the diagnosis of EP be based on the positive identification of an EP mass if inappropriate use of MTX is to be avoided. In the event of a PUL, waiting 48 hours to determine the hCG ratio has been shown to be a safe management approach, which offers further reassurance if the ratio is incompatible with a viable IUP (3).
Different discriminatory zone cut-off values are not helpful for the diagnosis of EP (4), as many EPs have serum hCG levels below 1000 IU/L. In the event that the serum hCG is above the discriminatory zone, classifying a PUL as a “presumed EP” can hCG is above the discriminatory zone, classifying a PUL as a “presumed EP” again can be misleading. Even at serum hCG levels of > 2400 IU/L, there remains the possibility that an ongoing viable IUP may have been missed, particularly in the event that the uterus is axial or in the presence of fibroids (4). The pregnancy should remain classified as a PUL until serial serum hCG levels show the pregnancy is failed or the location of the pregnancy has been identified using follow-up ultrasound examinations. Single serum hCG measurements should not be used in isolation to diagnose EP, and certainly not dictate immediate intervention. It is the behavior of the serum hCG over time which is most helpful in guiding diagnosis and management in women with a PUL.
A further concern is the continued recommendation that uterine curettage be used as a diagnostic tool when a pregnancy has been classified as a PUL and when the hCG level is above a set discriminatory zone, or if the serum hCG fails to rise at a set rate over time (usually 48 hours). Use of uterine curettage risks disrupting ongoing viable IUPs.
We have previously examined protocols with different definitions of pregnancy non-viability using an hCG discriminatory zone or the hCG ratio (0/48 hours). This study showed that the use of these protocols was associated with a rate of potential inadvertent termination of pregnancy (TOP) of 12% (number of potential TOPs/total number of potential curettages performed) (5).
The use of both MTX and curettage has the potential to cause harm to a normally developing IUP. MTX should not be used unless a positive diagnosis of an EP has been made using TVS carried out by an experienced examiner. An exception is a PUL with plateauing serum hCG levels that fail to resolve. In this circumstance the correct management is not known and a randomized trial comparing curettage, MTX, and no intervention is needed to answer this question. For uncomplicated PUL, provided the initial TVS is performed by an experienced operator, a watch-and-wait approach for the management of a PUL should be outpatient based and has been shown to be safe and reduce the need for unnecessary intervention.
Fernando Infante, M.B.B.S., M.P.H., MRANZCOG ¹
Uche Menakaya, M.B.B.S. ¹
George Condous, M.D. ¹, ²
¹ Acute Gynaecology, Early Pregnancy and Advanced Endosurgery Unit, Sydney Medical School Nepean, University of Sydney, Nepean Hospital, NSW, Australia
² OMNI Gynaecological Care, Centre for Women’s Ultrasound and Early Pregnancy, St. Leonards Sydney, NSW, Australia
1. Practice Committee of the American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril 2013;100:638-44.
2. Jurkovic. hCG as a patient. Ultrasound Obstet Gynaecol 2010;36:395-99.
3. Condous G, Kirk E, Van Calster B, Van Huffel S, Timmerman D, Bourne T. Failing pregnancies of unknown location: a prospective evaluation of the human chorionic gonadotrophin ratio. BJOG 2006;113:521-27.
4. Condous G, Kirk E, Lu C, Van Huffel S, Gevaert O, De Moor B, et al. Diagnostic accuracy of varying discriminatory zones for prediction of ectopic pregnancy in women with a pregnancy of unknown location. Ultrasound Obstet Gynaecol 2005;26:770-5.
5. Condous G, Kirk E, Lu C, Van Calster B, Van Huffel S, Timmerman D, et al. There is no role for uterine curettage in the contemporary diagnostic workup of women with a pregnancy of unknown location. Hum Reprod 2006;21:2706-10.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.12.013
The authors respond:
Thank you for your comments on the recent ASRM Practice Committee document titled “Medical treatment of ectopic pregnancy: a committee opinion.” The ASRM Practice Committee does not intend to promote techniques that risk interrupting a normal pregnancy. The Committee Opinion presents alternative approaches to diagnosing ectopic pregnancy and determining when to suspect a pregnancy is not normal and states that a definitive diagnosis should be made prior to treatment.
In the diagnosis of ectopic pregnancy discussed in the Committee Opinion, the approaches that are advocated include serial human chorionic gonadotropin (hCG) determinations, ultrasonographic examinations, and sometimes uterine curettage. The Committee Opinion does not indicate that a single serum hCG concentration above the discriminatory level with absence of an intrauterine gestation on transvaginal ultrasound is diagnostic of an ectopic pregnancy. Rather, the Committee Opinion states that “with hCG levels above the discriminatory zone of 1500-2500 IU/L a normal intrauterine pregnancy, defined as a gestational sac, should be visible by transvaginal ultrasound.” Furthermore, “the absence of an intrauterine gestational sac when the hCG concentration is above the discriminatory zone implies an abnormal gestation.” As stated in the document, in the case of multiple pregnancy, hCG levels are higher at an early stage of development than in singleton intrauterine gestations. It further discusses the rate of rise of serum hCG levels and their use in determining normal from abnormal values. The ASRM Committee Opinion states that every effort should be made to diagnose ectopic pregnancy definitively before medical treatment with methotrexate. The specific discriminatory zone may vary for different institutions depending on clinical expertise and specific characteristics of the serum hCG assay used, and serial serum hCG measurements are valuable to document either a growing, potentially viable, or a nonviable pregnancy. The use of uterine curettage is suggested as a tool to differentiate an abnormal intrauterine gestation from an ectopic pregnancy once the determination has been made that the pregnancy is not normal and thereby avoids exposure to methotrexate unnecessarily.
The diagnosis of ectopic pregnancy can be challenging and many factors need to be considered to achieve the correct diagnosis and avoid unnecessary treatments or avoid interruption of a normal pregnancy. Serial serum hCG measurements and transvaginal ultrasound assessments by an experienced examiner to avoid interruption of a normal pregnancy is a valid approach supported by the Committee Opinion.
On behalf of the Practice Committee:
Samantha Pfeifer, M.D.
Chair, ASRM Practice Committee
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.12.014