Do you need to definitively diagnose the location of a pregnancy of unknown location? The case for “yes”
2012; Elsevier BV; Volume: 98; Issue: 5 Linguagem: Inglês
10.1016/j.fertnstert.2012.09.033
ISSN1556-5653
Autores Tópico(s)Prenatal Screening and Diagnostics
ResumoPregnancy of unknown location (PUL) is a common diagnostic challenge. The primary diagnostic goal is to ensure that the PUL is nonviable prior to proceeding with any invasive procedures. In nonviable PUL, there are several diagnostic and treatment strategies, which are generally quite safe. However, the management option that provides the most definite diagnosis is uterine curettage. We advocate use of uterine curettage in all cases of nonviable PUL because it limits exposure to a chemotherapeutic agent to only those who need it and it allows for the most accurate information for counseling the patient on prognosis of future pregnancies. Pregnancy of unknown location (PUL) is a common diagnostic challenge. The primary diagnostic goal is to ensure that the PUL is nonviable prior to proceeding with any invasive procedures. In nonviable PUL, there are several diagnostic and treatment strategies, which are generally quite safe. However, the management option that provides the most definite diagnosis is uterine curettage. We advocate use of uterine curettage in all cases of nonviable PUL because it limits exposure to a chemotherapeutic agent to only those who need it and it allows for the most accurate information for counseling the patient on prognosis of future pregnancies. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/ruball-pregnancy-unknown-location/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/ruball-pregnancy-unknown-location/ Ectopic pregnancy (EP) continues to be a significant cause of maternal morbidity and mortality (1Barnhart K.T. Clinical practice. Ectopic pregnancy.N Engl J Med. 2009; 361: 379-387Crossref PubMed Scopus (322) Google Scholar). Complications associated with EP can be effectively reduced by early diagnosis and intervention. Transvaginal ultrasound facilitates the diagnosis of early gestations, and accurately differentiates intrauterine (IUP) and EP when serum beta human chorionic gonadotropin (hCG) levels are above 2000 IU/L, but can be nondiagnostic particularly when hCG levels are below this discriminatory zone (2Condous G. Kirk E. Lu C. Van Huffel S. Gevaert O. De Moor B. De Smet F. Timmerman D. Bourne T. Diagnostic accuracy of varying discriminatory zones for the prediction of ectopic pregnancy in women with a pregnancy of unknown location.Ultrasound Obstet Gynecol. 2005; 26: 770-775Crossref PubMed Scopus (113) Google Scholar, 3Barnhart K.T. Simhan H. Kamelle S.A. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone.Obstet Gynecol. 1999; 94: 583-587Crossref PubMed Scopus (129) Google Scholar). When transvaginal ultrasound fails to confirm the location of the pregnancy, the diagnosis of EP must be considered and further evaluation with serial serum quantitative hCG levels is required. Pregnancy of unknown location (PUL) is a descriptive term applied to women with a positive hCG and a nondiagnostic transvaginal ultrasound. There is agreement among experts that efforts should be made to achieve a final diagnosis whenever possible in women with a PUL (4Barnhart K. van Mello N.M. Bourne T. Kirk E. Van Calster B. Bottomley C. et al.Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome.Fertil Steril. 2011; 95: 857-866Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). However, definitions of acceptable final diagnoses vary in the literature. Some authors categorize the final outcomes of women with PUL into three groups including IUP, EP, and spontaneous abortion (SAB), while others identify four diagnostic strata: IUP, EP, failed PUL, and persisting PUL (4Barnhart K. van Mello N.M. Bourne T. Kirk E. Van Calster B. Bottomley C. et al.Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome.Fertil Steril. 2011; 95: 857-866Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). We argue that the latter two diagnostic categories should not be considered definitive outcomes as the location of the PUL has not been determined. A recent consensus statement acknowledged that final outcomes should be as definitive and comprehensive as possible, and should avoid use of present tense terms such as "persisting" (4Barnhart K. van Mello N.M. Bourne T. Kirk E. Van Calster B. Bottomley C. et al.Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome.Fertil Steril. 2011; 95: 857-866Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Additionally, the term PUL should be considered a classification rather than a final diagnosis. Importantly, the viability of the pregnancy should be determined prior to proceeding with further management. If there is a suspicion that a PUL in a stable patient could be a viable pregnancy, it is prudent to continue expectant management. In this way, no intervention will be performed that could harm an IUP. However, in nonviable PUL, definitive location can be achieved by performing uterine dilation and curettage (D&C), typically via suction. Neither expectant management nor presumptive methotrexate (MTX) use in nonviable PUL allows one to state with certainty whether the pregnancy was a SAB or an EP. We argue that it is important to achieve as definitive a diagnosis as possible in order to tailor appropriate treatment, avoid unnecessary side effects, and offer the most accurate counseling about prognosis of future pregnancies to the patient. When the hCG level is >2000 IU/L and no intrauterine gestation is visualized, or when there are deviations from expected rates of hCG rise or decline below 2000 IU/L as defined by previously published curves (1Barnhart K.T. Clinical practice. Ectopic pregnancy.N Engl J Med. 2009; 361: 379-387Crossref PubMed Scopus (322) Google Scholar), the pregnancy can confidently be considered nonviable and the diagnosis of EP is suspected but is not yet confirmed. Such observations should prompt intervention with D&C to distinguish a nonviable IUP (SAB) from an EP, and should be followed by the appropriate treatment. Frozen section evaluation of endometrial curettings has been reported to have high positive and negative predictive value, and may be useful in expediting the final diagnosis (5Spandorfer S.D. Menzin A.W. Barnhart K.T. LiVolsi V.A. Pfeifer S.M. Efficacy of frozen-section evaluation of uterine curettings in the diagnosis of ectopic pregnancy.Am J Obstet Gynecol. 1996; 175: 603-605Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Definitive diagnosis of SAB is confirmed by histopathologic identification of chorionic villi in the endometrial curettings, or post-evacuation serial decrease of serum hCG levels until negative. A uterine evacuation achieves both confirmation of the location of the PUL as well as treatment in those with an SAB. Conclusive evidence of EP is attained in the absence of chorionic villi in the endometrial curettings with a concomitant postoperative rise in hCG levels. In these patients, MTX can be administered with a clear indication. Though studies have shown that D&C only samples approximately 50% to 60% of the endometrium in nonpregnant patients (6Stock R.J. Kanbour A. Prehysterectomy curettage.Obstet Gynecol. 1975; 45: 537-541PubMed Google Scholar), its utility in pregnant patients is adequately sensitive. A study involving over 2,000 patients undergoing abortions at less than six weeks of gestation showed over 99% success using the manual vacuum aspirator (7Rock J.A. Jones H.W. Te Linde's operative gynecology.10th ed. Lippincott Williams & Wilkins, Philadelphia2008Google Scholar). Other studies looking specifically at miscarriage have reported similar success rates (8Niinimäki M. Jouppila P. Martikainen H. Talvensaari-Mattila A. A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage.Fertil Steril. 2006; 86: 367-372Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 9Zhang J. Gilles J.M. Barnhart K. Creinin M.D. Westhoff C. Frederick M.M. et al.A comparison of medical management with misoprostol and surgical management for early pregnancy failure.N Engl J Med. 2005; 353: 761-769Crossref PubMed Scopus (208) Google Scholar). Thus, curettage in patients who have a nonviable pregnancy should be able to diagnose whether it is intrauterine. In order to save time and avoid risks associated with a surgical procedure, clinicians often choose to abandon D&C in the diagnostic evaluation of PUL and either offer expectant management, as long as the patient remains stable, or administer MTX to all those suspected to have EP. This muddles the final diagnosis, at times precluding appropriate treatment and prognostic counseling of patients. There are several indirect, less invasive techniques than D&C in the diagnosis of nonviable PUL. However, they are fraught with lower accuracy and are not currently acceptable substitutions for a histologic diagnosis. Endometrial sampling by pipelle was demonstrated to have poor sensitivity and negative predictive value, making it an unsuitable substitute for D&C (10Barnhart K.T. Gracia C.R. Reindl B. Wheeler J.E. Usefulness of pipelle endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy.Am J Obstet Gynecol. 2003; 188: 906-909Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Noninvasive diagnostic tools including transvaginal ultrasound, hCG ratio, and serum progesterone levels may provide evidence to support a presumptive diagnosis of EP (11Fritz M.A. Speroff L. Ectopic pregnancy.in: Fritz M.A. Speroff L. Clinical gynecologic endocrinology and infertility. 8th ed. Lippincott Williams & Wilkins, Philadelphia2011: 1388-1396Google Scholar, 12Bignardi T. Condous G. Kirk E. Van Calster B. Van Huffel S. Timmerman D. Bourne T. Viability of intrauterine pregnancy in women with pregnancy of unknown location: prediction using human chorionic gonadotropin ratio vs. progesterone.Ultrasound Obstet Gynecol. 2010; 35: 656-661PubMed Google Scholar). However, several studies have demonstrated that despite advances in diagnostic tools, the presumptive diagnosis remains inaccurate in an unacceptably high number of cases (13Barnhart K.T. Katz I. Hummel A. Gracia C.R. Presumed diagnosis of ectopic pregnancy.Obstet Gynecol. 2002; 100: 505-510Crossref PubMed Scopus (84) Google Scholar, 14Shaunik A. Kulp J. Appleby D.H. Sammel M.D. Barnhart K.T. Utility of dilation and curettage in the diagnosis of pregnancy of unknown location.Am J Obstet Gynecol. 2011; 204: 130.e1-130.e6Abstract Full Text Full Text PDF Scopus (35) Google Scholar, 15Chung K. Chandavarkar U. Opper N. Barnhart K. Reevaluating the role of dilation and curettage in the diagnosis of pregnancy of unknown location.Fertil Steril. 2011; 96: 659-662Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). One of the first studies to evaluate the accuracy of the presumed diagnosis of EP using contemporary diagnostic modalities was a retrospective cohort analysis of 112 clinically stable women with hCG levels above 2,000 IU/L and no evidence of IUP on ultrasound, or with an abnormal rise or fall of serial hCG below 2,000 IU/L (13Barnhart K.T. Katz I. Hummel A. Gracia C.R. Presumed diagnosis of ectopic pregnancy.Obstet Gynecol. 2002; 100: 505-510Crossref PubMed Scopus (84) Google Scholar). Definitive diagnoses were confirmed by uterine curettage in the entire cohort. Overall, 38.4% (43 of 112) of the women were found to have SAB and 61.6% (69 of 112) were determined to have EP. Patients were more likely to be diagnosed with an EP if the initial hCG value was below 2,000 IU/L (relative risk 2.44; 95% confidence interval 1.07, 5.52). Ultrasound impressions were significantly associated with the final diagnosis (P=.001) but were not definitive. A more recent study of 173 patients with PUL who underwent D&C for abnormal patterns of serial hCG (rise, fall, or plateau) found that the presumptive diagnosis of EP was incorrect in 47.4% of cases (14Shaunik A. Kulp J. Appleby D.H. Sammel M.D. Barnhart K.T. Utility of dilation and curettage in the diagnosis of pregnancy of unknown location.Am J Obstet Gynecol. 2011; 204: 130.e1-130.e6Abstract Full Text Full Text PDF Scopus (35) Google Scholar). While preoperative factors including rise in hCG and ultrasound identification of free fluid or thin endometrial lining did improve the prediction of EP diagnosis, definitive location of the pregnancy could not be adequately achieved using these tools alone. In this report, transvaginal ultrasound was found to have a false-positive rate of 11% for EP and 40% for SAB. In a larger study of 387 patients with PUL, D&C was performed if the hCG level was >2,000 IU/L and no intrauterine gestation was visualized, or when there were deviations from expected rates of hCG rise (<50% increase in 2 days) or decline ( 2,000 mIU/mL, a finding that was consistent across studies. Thus, the role of D&C in the contemporary diagnosis of PUL continues to be important.Table 1Final diagnosis of patients with presumed EP.Final diagnosisSAB (%)EP (%)Barnhart 13Barnhart K.T. Katz I. Hummel A. Gracia C.R. Presumed diagnosis of ectopic pregnancy.Obstet Gynecol. 2002; 100: 505-510Crossref PubMed Scopus (84) Google Scholar All subjects43 (38.4)69 (61.6) hCG 2000 mIU/mL19 (54.3)16 (45.7)Shaunik 14Shaunik A. Kulp J. Appleby D.H. Sammel M.D. Barnhart K.T. Utility of dilation and curettage in the diagnosis of pregnancy of unknown location.Am J Obstet Gynecol. 2011; 204: 130.e1-130.e6Abstract Full Text Full Text PDF Scopus (35) Google Scholar All subjects66 (38.2)107 (61.8) hCG 2000 mIU/mL26 (65.0)14 (35.0)Chung 15Chung K. Chandavarkar U. Opper N. Barnhart K. Reevaluating the role of dilation and curettage in the diagnosis of pregnancy of unknown location.Fertil Steril. 2011; 96: 659-662Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar All subjects86 (26.8)235 (73.2) hCG 2000 mIU/mL54 (62.8)72 (30.6)Note: SAB = spontaneous abortion; EP = ectopic pregnancy; hCG = serum human chorionic gonadotropin. Open table in a new tab Note: SAB = spontaneous abortion; EP = ectopic pregnancy; hCG = serum human chorionic gonadotropin. Some authors argue that there is no role for routine use of D&C in the diagnostic evaluation of PUL, and that MTX may be administered once non-viability is established. Though resolution of the pregnancy can be achieved in this manner, failure to ascertain an accurate final diagnosis may lead to unnecessary exposure to MTX in nearly up to 50% of cases and has broad implications in both clinical and research arenas (Table 2). Though MTX may still be necessary postcurettage, less patients will be exposed to its risks and a more accurate treatment plan and prognosis will be accomplished if D&C is done first.Table 2Negative consequences of incorrectly presuming diagnosis of EP.Consequences related to MTX exposure The MTX syndrome embryopathy IUFD/SAB Delay of subsequent attempts to conceive to allow methotrexate washout Risk of serious side effects/death Possible effect on ovarian reserveConsequences related to presuming EP diagnosis Artificial increase in reported MTX success Legal ramifications if a complication arises Unnecessarily increased surveillance with future pregnancies Inaccurate counseling regarding future pregnancy prognosis Psychological issues: stigma, anxiety, depression Inaccurate epidemiological statistics Misclassification bias in clinical researchNote: EP = ectopic pregnancy; IUFD = intrauterine fetal demise; SAB = spontaneous abortion; MTX = methotrexate. Open table in a new tab Note: EP = ectopic pregnancy; IUFD = intrauterine fetal demise; SAB = spontaneous abortion; MTX = methotrexate. There is a chance that a PUL will resolve or that a final diagnosis of SAB versus EP will become clear as a stable patient is followed expectantly. In one study of 135 women with PUL, 50% resolved spontaneously (16Banerjee S. Aslam N. Zosmer N. Woelfer B. Jurkovic D. The expectant management of women with early pregnancy of unknown location.Ultrasound Obstet Gynecol. 1999; 14: 231-236Crossref PubMed Scopus (97) Google Scholar). Another group examined women with EP who were managed expectantly, and found an 88% spontaneous resolution rate (17Trio D. Strobelt N. Picciolo C. Lapinski R.H. Ghidini A. Prognostic factors for successful expectant management of ectopic pregnancy.Fertil Steril. 1995; 63: 469-472PubMed Scopus (93) Google Scholar). However, there are three issues with this management strategy. First, the subgroup of patients that meet criteria to be followed expectantly is small. One study found that the greatest chance of success occurred with an initial hCG level of <200 mIU/mL (18Korhonen J. Stenman U.H. Ylöstalo P. Serum human chorionic gonadotropin dynamics during spontaneous resolution of ectopic pregnancy.Fertil Steril. 1994; 61: 632-636PubMed Scopus (107) Google Scholar). Second, there is a risk of tubal rupture. Though rare, especially with properly selected patients, it could have serious consequences if it occurs. Third, if spontaneous resolution does occur, the precise location of the nonviable PUL remains unknown, which impacts counseling on future pregnancy prognosis. Serious complications from D&C are rare, occurring in less than 1 in 100 women undergoing abortions (7Rock J.A. Jones H.W. Te Linde's operative gynecology.10th ed. Lippincott Williams & Wilkins, Philadelphia2008Google Scholar), to 1.7% of nonpregnant patients (19MacKenzie I.Z. Bibby J.G. Critical assessment of dilatation and curettage in 1029 women.Lancet. 1978; 2: 566-568Abstract PubMed Scopus (146) Google Scholar). Per Rock and Jones (7Rock J.A. Jones H.W. Te Linde's operative gynecology.10th ed. Lippincott Williams & Wilkins, Philadelphia2008Google Scholar), specific complications include uterine perforation (0.2 per 100 abortions), hemorrhage (0.5 to 4.9 of 100 abortions, with only 0.06 of 100 abortions necessitating blood transfusion), cervical injury (0.01 to 1.6 of 100 abortions), infection (<1 of 100 abortions), retained products of conception (<1 of100 abortions), anesthesia risks, and Asherman syndrome. The latter two do not have precise incidence rates for this particular procedure, due to a paucity of prospective studies, but are not common in the literature. In addition, the probability that the patient will be diagnosed with EP, and thus will require MTX treatment subsequent to the D&C procedure, is high. As shown above, the diagnosis of EP was confirmed in 50% or more patients undergoing D&C (13Barnhart K.T. Katz I. Hummel A. Gracia C.R. Presumed diagnosis of ectopic pregnancy.Obstet Gynecol. 2002; 100: 505-510Crossref PubMed Scopus (84) Google Scholar, 14Shaunik A. Kulp J. Appleby D.H. Sammel M.D. Barnhart K.T. Utility of dilation and curettage in the diagnosis of pregnancy of unknown location.Am J Obstet Gynecol. 2011; 204: 130.e1-130.e6Abstract Full Text Full Text PDF Scopus (35) Google Scholar, 15Chung K. Chandavarkar U. Opper N. Barnhart K. Reevaluating the role of dilation and curettage in the diagnosis of pregnancy of unknown location.Fertil Steril. 2011; 96: 659-662Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Thus, the patient must be made aware that she may be exposed to the risks of MTX regardless of whether D&C is performed or not. However, it also needs to be made clear that she may be able to avoid MTX's risks, plus achieve an answer regarding where her pregnancy is located. It is difficult to perform a direct comparison of the benefit-to-risk balance between the three diagnostic and treatment options, but the risks associated with presumptive MTX treatment are delineated below. Overall, though minor side effects are not uncommon, the risk of serious complications or consequences of MTX appears rare. The effects of MTX exposure must be considered in the decision to treat nonviable PUL as presumed EP. Specifically, the patient must be counseled regarding its effects on the rare case of incorrectly diagnosed IUPs and the risk of serious complications. In addition, several groups have raised questions regarding whether timing of subsequent pregnancy or impact on future ovarian reserve should be considered or altered after MTX. It is important to emphasize that PUL should first and foremost be determined to be nonviable prior to any further interventions, whether surgical or medical. There are grave consequences to either; in essence, termination of pregnancy occurs when D&C is performed in a viable PUL, and medical risks exist if MTX is given to a pregnancy ultimately diagnosed as intrauterine. Again, these risks are mitigated as long as any intervention is preceded by confirmation of nonviability of the pregnancy. However, there are rare occasions when a subsequent viable IUP is diagnosed after administration of MTX. MTX is associated with an established embryopathy, described extensively in the literature, usually in association with misoprostol for elective abortion or in the form of another folic acid antagonist, aminopterin. However, there have been multiple reports published on the use of MTX alone and the constellation of abnormalities constituting the syndrome (20Nurmohamed L. Moretti M. Schecter T. Einarson A. Johnson D. Lavigne S. Erabara A. Koren G. Finkelstein Y. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic.AJOG. 2011; 205: 533.e1-533.e3Abstract Full Text Full Text PDF Scopus (44) Google Scholar, 21Poggi S. Ghidini A. Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiagnosis of ectopic pregnancy.Fert Steril. 2011; 96: 669-671Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 22Addar M. Methotrexate embryopathy in a surviving intrauterine fetus after presumed diagnosis of ectopic pregnancy: case report.J Obstet Gynaecol Can. 2004; 26: 1001-1003Abstract Full Text PDF PubMed Scopus (31) Google Scholar, 23Nguyen C. Duhl A. Escallon C. Blakemore K. Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester.Obstet Gynecol. 2002; 99: 599-602Crossref PubMed Scopus (65) Google Scholar, 24Corona-Rivera J. Rea-Rosas A. Santana-Ramirez A. Acosta-Leon J. Hernandez-Rocha J. Miguel-Jimenez K. Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome.Am J Med Genet. 2010; 152A: 1741-1746Crossref PubMed Scopus (21) Google Scholar, 25Piggott K. Sorbello A. Riddle E. DeCampli W. Congenital cardiac defects: a possible association of aminopterin syndrome and in utero methotrexate exposure?.Pediatr Cardiol. 2011; 32: 518-520Crossref PubMed Scopus (25) Google Scholar, 26Feldkamp M. Carey J. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy.Teratology. 1993; 47: 533-539Crossref PubMed Scopus (165) Google Scholar). The majority of women involved were being treated for rheumatologic disease, but studies did include women whose indication was for EP treatment or termination. Though the presentation is varied, the MTX syndrome consists of intrauterine growth restriction (IUGR), craniofacial, skeletal, and cardiac abnormalities; there have also been several reports implicating MTX as a teratogen associated with pulmonary, genitourinary, and gastrointestinal anomalies. The syndrome has been reported after first trimester exposure to MTX at oral doses as low as 7.5 mg for as little as two days (23Nguyen C. Duhl A. Escallon C. Blakemore K. Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester.Obstet Gynecol. 2002; 99: 599-602Crossref PubMed Scopus (65) Google Scholar) and after single exposure to a 50 mg intramuscular dose (20Nurmohamed L. Moretti M. Schecter T. Einarson A. Johnson D. Lavigne S. Erabara A. Koren G. Finkelstein Y. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic.AJOG. 2011; 205: 533.e1-533.e3Abstract Full Text Full Text PDF Scopus (44) Google Scholar). For rheumatologic disease treatment in pregnancy, several authors have postulated that a threshold MTX dose of 10 mg per week between 6 to 8 weeks of gestation is the lower limit to produce abnormalities (26Feldkamp M. Carey J. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy.Teratology. 1993; 47: 533-539Crossref PubMed Scopus (165) Google Scholar, 27Donnenfield A.E. Methotrexate exposure prior and during pregnancy.Teratology. 1994; 49: 79-81Crossref PubMed Scopus (130) Google Scholar), based on their case series and review of the literature including abnormalities associated with the aminopterin syndrome (which shares clinical anomalies with the MTX syndrome). Based on case reports in the literature, it appears that there is anywhere from no increase in risk to up to 24% to 29% risk of fetal anomaly after first trimester MTX exposure, including continuous low MTX doses (<20 mg weekly) (28Lloyd M.E. Carr M. McElhatton P. Hall G.M. Hughes R.A. The effects of methotrexate on pregnancy, fertility and lactation.Q J Med. 1999; 92: 551-563Crossref Scopus (183) Google Scholar, 29Martinez Lopez J.A. Loza E. Carmona L. Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding).Clin Exp Rheumatol. 2009; 27: 678-684PubMed Google Scholar). Though the rate of viable IUPs erroneously diagnosed as EP is not clearly known, the initial diagnosis of EP is inaccurate approximately 30% to 50% of the time (with the caveat that the ultimate diagnosis in the vast majority of these case is SAB) (13Barnhart K.T. Katz I. Hummel A. Gracia C.R. Presumed diagnosis of ectopic pregnancy.Obstet Gynecol. 2002; 100: 505-510Crossref PubMed Scopus (84) Google Scholar). Thus, the importance of definitively defining the location of a PUL reduces the chance that empiric MTX treatment could result in a malformed fetus and infant. Viable IUPs mistakenly diagnosed as ectopic pregnancies and thus exposed to MTX appear to have a higher risk of SAB (20Nurmohamed L. Moretti M. Schecter T. Einarson A. Johnson D. Lavigne S. Erabara A. Koren G. Finkelstein Y. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic.AJOG. 2011; 205: 533.e1-533.e3Abstract Full Text Full Text PDF Scopus (44) Google Scholar, 26Feldkamp M. Carey J. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy.Teratology. 1993; 47: 533-539Crossref PubMed Scopus (165) Google Scholar, 28Lloyd M.E. Carr M. McElhatton P. Hall G.M. Hughes R.A. The effects of methotrexate on pregnancy, fertility and lactation.Q J Med. 1999; 92: 551-563Crossref Scopus (183) Google Scholar). This is unsurprising due to MTX's mechanism of action; in fact, this is purposely exploited in its use as an abortifacient. Based on a case series examining the outcome of 8 pregnancies, there is an increased risk of subsequent SAB risk of up to 38% after high-dose MTX given for EP, which occurs 7 to14 days after exposure (20Nurmohamed L. Moretti M. Schecter T. Einarson A. Johnson D. Lavigne S. Erabara A. Koren G. Finkelstein Y. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic.AJOG. 2011; 205: 533.e1-533.e3Abstract Full Text Full Text PDF Scopus (44) Google Scholar). Though the majority of pregnancies after MTX exposure will be healthy, the timing of a woman's next pregnancy must be discussed due to MTX's known teratogenicity and persistence in tissues. Since MTX is a chemotherapeutic agent, it is important to understand its pharmacokinetics to determine when a subsequent pregnancy may be safely attempted. MTX is a dicarboxylic weak acid that undergoes a triphasic clearance from the plasma after intravenous injection (30Bleyer W.A. Methotrexate: clinical pharmacology, current status and therapeutic guidelines.Cancer Treatment Reviews. 1977; 4: 87-101Abstract Full Text PDF PubMed Scopus (164) Google Scholar). In the first phase, the half-life is 2.06 ± 0.16 hours, which increases to 3.49 ± 0.55 hours during its second phase (31Huffman D.H. Wan S.H. Azarnoff D.L. Hogstraten B. Pharmacokinetics of methotrexate.Clin Pharmacol Ther. 1973; 14: 572-579Crossref PubMed Scopus (157) Google Scholar), and finally to 10.4 ± 1.8 hours in its terminal half-life (32Stoller R.G. Hande K.R. Jacobs S.
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