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  VOL. 111, NO. 6, JUNE 2008 OBSTETRICS & GYNECOLOGY 1479 CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIAN – GYNECOLOGISTS NUMBER 94, JUNE 2008 (Replaces Practice Bulletin Number 3, December 1998) This Practice Bulletin was devel-oped by the ACOG Committee onPractice Bulletins—Gynecologywith the assistance of DonaldFylstra,MD. The information isdesigned to aid practitioners inmaking decisions about appropriateobstetric and gynecologic care.These guidelines should not be con-strued as dictating an exclusivecourse of treatment or procedure.Variations in practice may be war-ranted based on the needs of theindividual patient,resources,andlimitations unique to the institutionor type of practice. Medical Management of Ectopic Pregnancy  In the United States,ectopic pregnancy accounts for 2% of all first-trimester  pregnancies and 6% of all pregnancy-related deaths; it is the leading cause of maternal death in the first trimester (1). Early detection of ectopic pregnancycan lead to successful management without surgery. Methotrexate,a folic acid antagonist,can be used successfully to treat early,nonruptured ectopic preg-nancy. The purpose of this document is to review the risks and benefits of theuse of methotrexate in the management of ectopic pregnancy. Background Incidence  The true incidence of ectopic pregnancy is difficult to estimate because manypatients are treated in an outpatient setting. In 1992,ectopic pregnanciesaccounted for 2% of pregnancies (2). The prevalence of ectopic pregnancyamong women presenting to an emergency department with first-trimester vagi-nal bleeding,abdominal pain,or both has been reported to be as high as 18%(3). Etiology  Nearly all ectopic pregnancies (97%) are implanted within the fallopian tube,although implantation can occur within the abdomen,cervix,ovary,or uterinecornua. One common factor for the development of an ectopic pregnancy is apathologic fallopian tube. Causes for such pathology include tubal surgery,gen-ital tract infections leading to pelvic inflammatory disease,previous ectopicpregnancy,and in utero exposure to diethylstilbestrol (4). One third of preg-nancies that occur after sterilization failure are ectopic implantations (5,6),andsuch pregnancies account for 10% of all ectopic pregnancies (7). Additionally,  ACOG PRACTICE BULLETIN  THE AMERICAN COLLEGE OFOBSTETRICIANS ANDGYNECOLOGISTS WOMEN  ’  S HEALTH CARE PHYSICIANS   1480  ACOG Practice Bulletin Medical Management of Ectopic Pregnancy  OBSTETRICS & GYNECOLOGY  one third of pregnancies after an ectopic pregnancy arealso ectopic implantations (7). Other risk factors for thedevelopment of ectopic pregnancy include infertility,useof assisted reproductive technologies,previous pelvic orabdominal surgery,and smoking. Diagnosis  Traditionally,the diagnosis of ectopic pregnancy hasbeen based on the clinical signs and physical symptomsof tubal rupture. However,if ectopic pregnancy is diag-nosed before rupture,conservative treatment is anoption. By measuring serial human chorionic gonad-otropin (hCG) levels and using serial ultrasonography,ectopic pregnancy can be diagnosed before rupture. Atleast one half of women in whom ectopic pregnancy isdiagnosed have no identifiable risk factors or initialdefinitive physical findings. Early diagnosis is aided bya high index of suspicion. Every sexually active repro-ductive-aged woman who presents with abdominal pain or vaginal bleeding should be screened for preg-nancy (8,9). Transvaginal ultrasonography should be consideredfor all women with suspected early gestational patholo-gy. An initial transvaginal ultrasound examination can beused to visualize an intrauterine pregnancy or a definiteextrauterine gestation,or it can be nondiagnostic (10).The woman with a nondiagnostic ultrasound examina-tion result (nothing seen to confirm a gestation inside oroutside the uterus) requires further evaluation,includingmeasurement of serum hCG levels. Accurate gestationalage calculation,rather than an absolute level of hCG,isthe best determinant of when a normal pregnancy shouldbe seen within the uterus with transvaginal ultrasonogra-phy. Therefore,if the precise gestational age is known,asin the case of patients conceiving with ovulation induc-tion or embryo transfer,the failure to detect a gestationalsac within the uterus by 24 days or later after conceptionis presumptive evidence of an abnormal pregnancy (13).Without such precise gestational dating,the serum levelof hCG must be used in order to interpret a nondiagnos-tic ultrasonogram. The “discriminatory zone”of hCG isthat level of hCG,generalized 1,500–2,000 mIU/mL(International Reference Preparation) (11,12),whichwhen reached is associated with the appearance,ontransvaginal ultrasonography,of a normal singletonintrauterine gestation.Historically,detection of an intrauterine sac has ledto the presumptive exclusion of ectopic pregnancy.However,the incidence of heterotopic pregnancyappears to have increased with the use of assisted repro-ductive techniques. It has been reported to be as high as1% in some series (14),although the overall incidence of heterotopic pregnancy probably is much lower.If the hCG level is higher than the discriminatoryzone,and the transvaginal ultrasound examination resultis nondiagnostic,ectopic pregnancy is likely (15). How-ever,multiple gestations have higher hCG levels thansingletons at any given gestational age and may lead tohCG levels well above 2,000 mIU/mL before ultrasoundrecognition (13). Therefore,if a multiple gestation islikely,such as in a woman who has conceived withassisted reproductive technology,the discriminatoryzone should be reevaluated. Serum progesterone level determination may helpconfirm an ectopic pregnancy diagnosis. Serum proges-terone values are independent of hCG levels,and anabnormal progesterone level is consistent with an abnor-mal,failing pregnancy but does not identify the site of the pregnancy (failed intrauterine or ectopic pregnancy).A serum progesterone level less than 5 ng/mL has aspecificity of 100% in confirming an abnormal pregnan-cy (16). Serum progesterone levels higher than 20ng/mL usually are associated with normal intrauterinepregnancies,and levels between 5 ng/mL and 20 ng/mLare considered equivocal. Most ectopic pregnancies areassociated with a serum progesterone level between10 ng/mL and 20 ng/mL,limiting the clinical utility of this assessment. In the absence of a diagnostic ultrasound examina-tion result or a low serum progesterone level consistentwith a failed pregnancy,serial hCG levels must be used toevaluate an ongoing pregnancy. With 99% sensitivity inearly pregnancy,an increase in serum hCG of less than53% in 48 hours confirms an abnormal pregnancy (17).Therefore,a nondiagnostic ultrasound examination resultwith a serum progesterone level less than 5 ng/mL and aninappropriate increase in hCG are each associated with anabnormal pregnancy. If necessary,endometrial samplingcan be used to differentiate between a failed intrauterinepregnancy and ectopic pregnancy by confirming the pres-ence or absence of intrauterine chorionic villi.If a woman has an initial nondiagnostic ultrasoundexamination result,an equivocal or normal serum pro-gesterone level,and an appropriately increasing hCGlevel,and she remains clinically stable,a transvaginalultrasound examination should be repeated when thehCG reaches the discriminatory zone. The same diag-nostic possibilities then should be considered. Methotrexate  Methotrexate is an antimetabolite that binds to the cat-alytic site of dihydrofolate reductase,interrupting thesynthesis of purine nucleotides and the amino acids ser-ine and methionine,thus inhibiting DNA synthesis andrepair and cell replication. Methotrexate affects actively  proliferating tissues such as bone marrow,buccal andintestinal mucosa,respiratory epithelium,malignantcells,and trophoblastic tissue. Systemic methotrexatehas been used to treat gestational trophoblastic diseasesince 1956 and was first used to treat ectopic pregnancyin 1982 (18). The overall success for treatment of ectopicpregnancy using systemic methotrexate in observationalstudies ranges from 71.2% to 94.2% (7,19). Successdepends on the treatment regimen used,gestational age,and hCG level. A systematic review of several observa-tional studies reported a failure rate of 14.3% or higherwith single-dose methotrexate when pretreatment hCGlevels are higher than 5,000 mIU/mL,compared with a3.7% failure rate for hCG levels less than 5,000 mIU/mL(20). If hCG levels are higher than 5,000 mIU/mL,mul-tiple doses may be appropriate (21). Clinical Considerations andRecommendations Who are candidates for treatment with methotrexate? Methotrexate therapy can be considered for thosewomen with a confirmed,or high clinical suspicion of,ectopic pregnancy who are hemodynamically stablewith an unruptured mass. A candidate for methotrexatetreatment must be able to comply with follow-up sur-veillance. Because methotrexate affects all rapidlydividing tissues within the body,including bone mar-row,the gastrointestinal mucosa,and the respiratoryepithelium,it should not be given to women with blooddyscrasias or active gastrointestinal and respiratory dis-ease. Methotrexate is directly toxic to the hepatocytesand is cleared from the body by renal excretion; there-fore,it should not be used in women with liver orkidney disease. Contraindications for the use of methotrexate are listed in the box,“Contraindications toMethotrexate Therapy.”Before administering metho-trexate,a woman should have a confirmed normalserum creatinine level,normal liver transaminases,andno bone marrow dysfunction indicated by significantanemia,leucopenia,or thrombocytopenia. Typically,these laboratory tests are repeated 1 week after admin-istering methotrexate to evaluate any possible impact onrenal,hepatic,and hematologic function.  How is methotrexate used in the manage- ment of ectopic pregnancy? Three protocols are published for the administration of methotrexate to treat ectopic pregnancy:1) single dose, VOL. 111, NO. 6, JUNE 2008  ACOG Practice Bulletin Medical Management of Ectopic Pregnancy   1481 Contraindications to Medical Therapy Absolute contraindicationsBreastfeedingOvert or laboratory evidence of immunodeficiency Alcoholism, alcoholic liver disease, or other chronicliver diseasePreexisting blood dyscrasias, such as bone marrowhypoplasia, leukopenia, thrombocytopenia, or sig-nificant anemiaKnown sensitivity to methotrexateActive pulmonary diseasePeptic ulcer diseaseHepatic, renal, or hematologic dysfunctionRelative contraindicationsGestational sac larger than 3.5 cmEmbryonic cardiac motion Methotrexate Treatment Protocols Single-dose regimen:  * Single dose MTX 50 mg/m 2 IM day 1Measure hCG level on posttreatment days 4 and 7Check for 15% hCG decrease between days 4 and 7. Then measure hCG level weekly until reaching thenonpregnant level.If results are less than the expected 15% decrease, re-administer MTX 50 mg/m 2 and repeat hCG measure-ment on days 4 and 7 after second dose. This can berepeated as necessary.If, during follow-up, hCG levels plateau or increase,consider repeating MTX. Two-dose regimen:  † Administer 50 mg/m 2 IM on day 0.Repeat 50 mg/m 2 IM on day 4.Measure hCG levels on days 4 and 7, and expect a15% decrease between days 4 and 7.If the decrease is greater than 15%, measure hCG levels weekly until reaching nonpregnant level.If less than a 15% decrease in hCG levels, readministerMTX 50 mg/m 2 on days 7 and 11, measuring hCGlevels. (continued)  1482  ACOG Practice Bulletin Medical Management of Ectopic Pregnancy  OBSTETRICS & GYNECOLOGY  2) two dose,and 3) fixed multidose (see the box,“Metho-trexate Treatment Protocols”). The single 50 mg/m 2 doseregimen is the simplest and has been shown by some to beas effective as the fixed multidose regimen,eliminatingthe need for folinic acid rescue to minimize side effects(22). However,a recent meta-analysis has shown the fixedmultidose regimen to be more effective,especially intreating women with more advanced gestations and thosewith embryonic cardiac activity (19). A recent prospectivestudy evaluating a two-dose regimen found high patientsatisfaction,few side effects,and 87% treatment success(23).Methotrexate also can be used after surgical man-agement of an ectopic pregnancy. Treatment failure (per-sistent ectopic pregnancy) ranges from 2% to 11% afterlaparotomy and salpingostomy,and from 5% to 20%after laparoscopic salpingostomy (7). A nonruptured,persistent ectopic pregnancy after salpingostomy diag-nosed by monitoring serial hCG levels almost uniformlyresolves with a single dose of methotrexate. In one ran-domized trial,the empiric administration of a single doseof methotrexate immediately after laparoscopic salpin-gostomy essentially eliminated the risk of subsequentpersistent ectopic pregnancy (24). However,manywomen would need to be treated with methotrexate toprevent one persistent ectopic pregnancy; therefore,monitoring with serum hCG levels may be more useful(25). What surveillance is needed after methotrex- ate treatment? With any conservative surgical or medical treatment of ectopic pregnancy,women require close monitoring toensure disappearance of trophoblastic activity and elim-ination of the possibility of persistent ectopic pregnancyafter treatment with methotrexate. Persistent tropho-blastic activity is confirmed by serially measuring hCGlevels. The hCG level may increase initially to levelshigher than the pretreatment level,but then should pro-gressively decrease to reach a nonpregnant level (26).Failure of the hCG level to decrease by at least 15% fromday 4 to day 7 after methotrexate administration is con-sidered treatment failure. Therapy with either additionalmethotrexate administration or surgical intervention isrequired. Posttreatment hCG levels should be monitoreduntil a nonpregnancy level is reached. What are the potential side effects from sys- temic methotrexate administration? Methotrexate morbidity usually is dose and treatmentduration dependent. Because methotrexate affects rapid-ly dividing tissues,gastrointestinal side effects,such asnausea,vomiting,and stomatitis,are the most common.Therefore,women treated with methotrexate should beadvised not to use alcohol and nonsteroidal antiinflam-matory drugs (NSAIDs). Elevation of liver enzymes usu-ally is seen only with multidose regimens and resolvesafter discontinuing methotrexate use or increasing therescue dose of folinic acid (27). Alopecia is a rare sideeffect with the doses used to treat ectopic pregnancy.Women should report any fever or respiratory symptomsbecause pneumonitis has been reported.It is not unusual for women treated with methotrex-ate to experience abdominal pain 2–3 days after admin-istration,presumably from the cytotoxic effect of thedrug on the trophoblast tissue,causing tubal abortion. Inthe absence of signs and symptoms of overt tubal ruptureand significant hemoperitoneum,this pain usually can be Methotrexate Treatment Protocols (continued)  Two-dose regimen:  † (continued) If hCG levels decrease 15% between days 7 and 11,continue to monitor weekly until nonpregnant hCGlevels are reached.If the decrease is less than 15% between days 7 and11, consider surgical treatment. Fixed multidose regimen:  ‡ Administer MTX 1 mg/kg IM (on days 1, 3, 5, 7), alternatedaily with folinic acid 0.1 mg/kg IM (on days 2, 4, 6, 8).Measure hCG levels on MTX dose days and continueuntil hCG has decreased by 15% from its previousmeasurement. The hCG level may increase initially above pretreatment value, but after 15% decrease, monitor hCG levels weekly until reaching the nonpregnant level.If the hCG level plateaus or increases, consider repeat-ing MTX using the regimen described. MTX, methotrexate; IM, intramuscular; hCG, human chorionicgonadotropin.*Stovall TG, Ling FW. Single-dose methotrexate: an expanded clini-cal trial. Am J Obstet Gynecol 1993;168:1759–62; discussion1762–5. (Level II-3) † Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, ChakhtouraN. Use of “2-dose” regimen of methotrexate to treat ectopic preg-nancy. Fertil Steril 2007;87:250–6. (Level III) ‡ Rodi IA, Sauer MV, Gorrill MJ, Bustillo M, Gunning JE, Marshall JR,et al. The medical treatment of unruptured ectopic pregnancy withmethotrexate and citrovorum rescue: preliminary experience. FertilSteril 1986;46:811–3. (Level III)
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