We read the letter by Bodur et al written in regard of our article “Unforeseen consequences of the increasing rate of cesarean deliveries: early placenta accreta and cesarean scar pregnancy: a review” in the American Journal of Obstetrics and Gynecology 2012; July 207:14-29 dealing with the complications after administration of a single systemic methotrexate (MTX) injection for the treatment of cesarean scar pregnancy (CSP).

We appreciate the effort invested in evaluating our review; and are confident, that the main objective of their letter was to uncover the genuine value of single dose systemic MTX use as a first line agent in certain cases of CSP. Our findings based on the reviewed literature were that such treatment of CSP is associated with a high complication rate (62.1%) requiring 1 or more follow-up treatment(s), although their calculations resulted in a lower complication rate (36.1%).

In light of their analysis, we re-reviewed our data; the findings are summarized in the attached table. Every article cited in the letter of Bodur et al was specifically addressed in the table and in this letter. Indeed, we misclassified 16 cases contained in 8 articles (reference citations 54, 60, 72, 212, 213, 217, 220, and 248), in which their first line treatment management was in fact not, or not only systemic injection of MTX, but it was MTX combined with additional treatments. Needless to say, it was a mistake in our tabulation, and we have not deliberately done so. These cases were removed from the calculation of the MTX complications (Table appears in the Correction). The cases in reference citations 81 and 120 deserve special explanation, which are also included in the table.

Several cases that Bodur et al considered as successfully treated were evaluated by us to be indeed unsuccessfully treated by the single intramuscular dose of MTX. In the table, we explained the reasons for every such case. These are legitimate issues of interpretation that can be meaningfully argued about in a scientific manner. As an example: when a multidose systemic MTX was administered in a preplanned fashion leading to success, we accepted this as successful MTX therapy (reference citations 240 and 247). However, when systemic MTX had to be repeated because of the failure to stop the heart, the raising serum human chorionic gonadotropin, the need for hospitalization, or the patient had symptoms because of the treatment (1 case each from reference citations 77, 207, 235, 239, and 241), we rightfully considered those as complicated cases. Our definition and criteria of complications, clearly stated in the article was, “Complications were defined as the immediate or delayed need for a secondary treatment.” The second dose/s of systemic MTX, in a delayed and unplanned fashion fits this statement.

The cases of intravenous MTX (in reference citation 120, Wang et al 2009) were not included by us in either group. However, it can be argued, that the effect of intravenous administration of a drug can easily be identical with its intramuscular injection; the difference between the 2 routes of administration is, that the intravenous drug reaches faster a higher serum concentration. Even by this more “aggressive” MTX administration 14 of the 21 patients had excess vaginal bleeding by our inclusion criteria and 2 had hysterectomies. This is the single largest number of patients that created the appearance of the discrepancies between our numbers and those of Bodur et al. To avoid further, unnecessary debate on the subject we removed these cases as complications placing them into the group of those cases, in which the first line treatment was not systemic MTX treatment in spite their clear and indirect support of our views.

As to the final and re-reviewed statistics included in our table we considered that 56 cases met our inclusion criteria for analysis. Fifteen cases were successfully treated by a single, first line dose of systemic MTX, while 41 were considered to require “immediate or delayed” additional, secondary treatment. Thus the rate of complications was 73.2%. Even if we extract all cases that, regardless of time-interval, needed an unplanned, secondary treatment with additional systemic administration of MTX, (ie, 4 cases within reference citations 207, 235, 239, and 241), the number of successfully treated cases would increase to 19 and those being unsuccessful drops to 37. According to the above, the computed complication rate would still be 66.1%. This rate would be even higher than the 62.1% reported in our article. In either scenario, the complication rate is much higher than 36.1% suggested by Bodur et al.

We therefore maintain that in patients with nonemergent cases of CSP, administering a single dose treatment of systemic MTX (inclusive of its intravenous administration) and waiting for it to stop the heart and lower the serum human chorionic gonadotropin, may lead to a continuing and growing gestation, but foremost in an increase of its vascularization; thus, presenting a potentially greater challenge to a subsequent, final treatment. Understandably, it also may lead to a realistic possibility of more complications clearly reflected in the literature. Therefore, echoed by the literature reviewed by us, such treatment should be avoided (or at least carefully considered) favoring its combination with other treatments to achieve the best outcome and fewest possible complications.

We thank Bodur et al for their observations that ultimately lead us to a more stringent analysis of the effects of systemic MTX administration in CSP and a reconfirmation of our conclusions.