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‘‘Watchful waiting’’ in ectopic pregnancies: a balance between reduced success rates and less methotrexate Many cases of ectopic pregnancy will spontaneously resolve, so that ‘‘watchful waiting’’ and b-hCG follow-up will separate true viable ectopic pregnancies from spontaneously resolving ectopic pregnancies. Withholding methotrexate in patients with spontaneously resolving ectopic pregnancies and administering it in only true viable ectopic pregnancies will no doubt decrease published success rates for this therapy. (Fertil Steril 2011;95:1159–60. 2011 by American Society for Reproductive Medicine.) Key Words: Ectopic pregnancies, methotrexate, spontaneously resolving ectopic pregnancies Methotrexate therapy has become the treatment of choice for nonruptured, hemodynamically stable ectopic pregnancies. Reported success rates are high and depend mostly on b-hCG levels. Success rates reported are 98.3% for b-hCG levels <1,000 mIU, whereas 68.2% success rates are reported for levels >15,000 mIU (1). Common protocols used for treatment are single- and doubledose methotrexate therapy. Barnhart et al. (2), in a meta-analysis comparing single-dose vs. repeat-dose methotrexate, found that the multiple dose is more effective (92.7% success rate for multiple dose vs. 88.1% for single dose), although it is associated with a higher rate of side effects. After an ultrasound scan and diagnosis of an ectopic mass <3.5 cm and the basic laboratory workup, methotrexate is administered (3). The American Society for Reproductive Medicine did not define the need for a time interval or repeat b-hCG testing before treatment once the diagnosis of ectopic pregnancy is confirmed (4). Stovall et al. (5) described a protocol for the treatment of ectopic pregnancies in an effort to minimize surgical interventions. In this protocol, an interval of 12–24 hours is used before repeat vaginal Ishai Levin, M.D.a Ziv Tsafrir, M.D.a Nili Sa’ar, M.Sc.b Joseph Lessing, M.D.a Amiram Avni, M.D.a Ronni Gamzu, M.D.a Benny Almog, M.D.a a Department of Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel b Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Received July 18, 2010; revised September 10, 2010; accepted October 13, 2010; published online November 10, 2010. I.L. has nothing to disclose. Z.T. has nothing to disclose. N.S. has nothing to disclose. J.L. has nothing to disclose. A.A. has nothing to disclose. R.G. has nothing to disclose. B.A. has nothing to disclose. N.S. participated in this study as required for partial fulfillment of her M.D. thesis. Reprint requests: Ishai Levin, M.D., Department of Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 69234, Israel (E-mail: ishai.levin@gmail.com).

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ultrasound and b-hCG testing. In cases in which an ectopic pregnancy mass <3.5 cm is found and b-hCG levels are rising or at plateau and are >2,000 mIU, methotrexate is administered. In essence, this protocol mandates the use of methotrexate where no contraindications for medical therapy exist and after a period of 12–24 hours of surveillance. This interval of b-hCG level follow-up might well be a critical issue in terms of success rates for methotrexate. Withholding this drug while observing stable patients may reveal a decrease in b-hCG levels and ectopic pregnancies that will spontaneously resolve, whereas patients with viable ectopic pregnancies will demonstrate rising levels of this hormone. As such, prompt treatment with methotrexate will increase success rates because patients with spontaneously resolving ectopic pregnancies will also be treated, whereas later administration will reduce success rates because the majority of treated patients will have viable ectopic pregnancies. We retrospectively collected data from charts of 700 patients admitted to the Department of Gynecology, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center with the diagnosis of ectopic pregnancies between January 1, 2001 and September 30, 2008. The local ethics committee approved this retrospective study. Patients who were hemodynamically unstable or had ectopic pregnancies with gestational cardiac activity or b-hCG levels >10,000 mIU were referred for immediate surgery. Four hundred one patients were candidates for follow-up or medical therapy. In stable patients, before medical treatment with methotrexate, we evaluated levels of b-hCG daily. Methotrexate was administered to asymptomatic patients when b-hCG levels were rising, and it was withheld when b-hCG levels fell by at least 15%, and the patient was discharged. In patients with plateau levels of b-hCG we repeated b-hCG level testing daily while the patient was hospitalized. Some asymptomatic patients were hospitalized and followed for up to 5 days before methotrexate administration or discharge because of fluctuating levels of b-hCG (average waiting period, 2.65 days). Of 401 patients who were candidates for conservative therapy, 186 (46.4%) were discharged without treatment after a spontaneous decrease in b-hCG levels was observed and after a maximum of 5 days of hospitalization. Two hundred fifteen patients (53.6%)

Fertility and Sterility Vol. 95, No. 3, March 1, 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

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TABLE 1 Follow-up time period and success rates for methotrexate in stable patients with ectopic pregnancies. Follow-up interval Variable No. of patients discharged daily/total No. of potential patients for MTX therapy Combined success rate, % (no. of patients available) No. of patients avoiding therapy

Admission

24 h (1 d)

48 h (2 d)

72 h (3 d)

96 h (4 d)

120 h (5 d)

27/27 153 99.2 (336)

33/60 93 88.8 (276)

34/94 59 85.2 (242)

26/120 33 80.6 (216)

23/143 10 76.2 (193)

10/153 0 73.8 (153)

NA

0

34

60

83

123

Note: MTX ¼ methotrexate. Levin. Correspondence. Fertil Steril 2011.

received methotrexate (single or double dose: 183 and 32 patients, respectively) during a follow-up period of at most 5 days. Complete data and daily hormone levels were available for 153 (of 186) patients in the ‘‘no treatment’’ group and 183 patients in the single-dose methotrexate group and are summarized in Table 1.

Treatment after 4 days of follow-up, on the other hand, would yield a success rate for methotrexate of only 76.2%. A greater proportion of patients will at this point have viable ectopic pregnancies according to plateau levels of b-hCG, but only 193 patients would be treated, and thus 83 patients avoid therapy.

It is clearly seen that a significant proportion of patients were candidates for methotrexate therapy but were finally discharged without treatment because they were asymptomatic and because plateau levels of b-hCG, which we continued to observe, finally declined. It is in these patients that methotrexate was withheld. Administering this drug in these patients would probably increase our success rate for this treatment while increasing the number of patients treated. Failure rates for ‘‘follow-up’’ treatment (patients who were readmitted for methotrexate therapy or surgery) were minimal and not changed with longer intervals of follow-up.

Waiting 5 days before treatment will decrease the methotrexate success rate to 73.8%, and 120 patients will be able to avoid therapy.

The combined ‘‘would-be’’ success rates for methotrexate are also shown in Table 1. This success rate combines success rate for patients who were treated with single-dose methotrexate and patients who would have received treatment according to protocol after 24 hours if they had been treated rather than observed. As demonstrated, administering methotrexate after a period of 24 hours to all patients would yield a success rate of 88.8%. At this time point, treatment would be given to all true viable ectopic pregnancies but also to 93 patients in whom continuing follow-up will reveal decreasing levels of b-hCG and probably an ectopic pregnancy that will spontaneously resolve. According to this protocol, 276 patients would have been treated.

It is this point exactly that is to be emphasized. Early administration of methotrexate yields high rates of success, as reported above. This is no doubt attributed to the efficacy of this drug, but it is also probably due to the fact that some ectopic pregnancies resolve spontaneously. The time necessary for ectopic pregnancies to resolve spontaneously is not obvious. This was our basic idea when we decided to observe patients for longer periods before the decision to treat. In conclusion, previous studies have no doubt demonstrated that methotrexate therapy for hemodynamically stable patients with ectopic pregnancies is successful. To minimize the number of patients treated when there is no need, longer intervals for repeat b-hCG testing are needed. Although reducing the number of patients treated, the success rates for methotrexate therapy will be decreased. Until specific guidelines for treatment are brought forward, the proportion of patients treated will be determined on one hand by wanting to achieve high rates of success and on the other hand by the ability to provide longer follow-up intervals.

REFERENCES 1. Lipscomb GH, Stovall TG, Ling FW. Nonsurgical treatment of ectopic pregnancy. N Engl J Med 2000;343:1325–9. 2. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy:

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a meta-analysis comparing ‘‘single dose’’ and ‘‘multidose‘‘ regimens. Obstet Gynecol 2003;101: 778–84. 3. Berek JS. Berek and Novak’s gynecology. 14th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.

4. American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy. Fertil Steril 2006;86:S96–102. 5. Stovall TG, Ling FW. Ectopic pregnancy. Diagnostic and therapeutic algorithms minimizing surgical intervention. J Reprod Med 1993;38:807–12.

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