ectopic pregnancy ( ep ) is a term used for implantation of blastocyst outside the natural cavity of uterus ( 1 , 2 ) . the prevalence of ep has been doubled since 1960 and comprises 2% of pregnancies diagnosed at the first trimester ( 3 ) . in the developing countries like iran , 10% of women diagnosed with ep , can not survive , as they refer to the hospital very late ( 4 ) . the prevalence of ep has increased owning to high occurrence of prior damage to the fallopian tubes , due to the abdominal operation ( 5 ) , infertility ( 6 ) , using artificial reproductive technology ( 7 ) , infections like chlamydia trachomatis ( 8) , and using contraception devices , which contains only progesterone ( 9 ) . considering high prevalence of ep , finding efficient and safe methods of treatment has gained top priority . if the patient s hemodynamic condition is stable , with no significant symptoms , and low free intraperitoneal fluid detected on ultrasound ( 10 ) , medical treatment is preferable in which the single dose of methotrexate ( mtx ) is prescribed in 34% - 69% of cases ( 11 ) . however , when the fallopian tubes remained unruptured , the medical treatment is preferable for preserving fertility ( 12 ) . also , medical treatment is more feasible , affordable , and accepted by patients . but it is not clear that which medical protocol ( single , double , or multiple doses ) is preferable . however , the success of multidose therapy is more than single dose in most of the studies ( 13 ) . some studies have found that double dose is preferable due to its few side effects ( 14 ) . there are few studies on comparing the effectiveness of single dose with double dose administration of mtx , therefore this study was designed to compare the effectiveness of single and double dose of mtx in treatment of ep . this research is a randomized controlled trial study conducted on 76 patients with ectopic pregnancy referring to imam khomeini hospital of ahvaz city , iran during 2012 - 2013 . the design of this study was approved by the ethics committee of ahvaz jundishapur university of medical sciences , ahvaz , iran ( reference number : ajums . imam khomeini hospital is specialty teaching hospital affiliated to the ahvaz jundishapur university of medical sciences and is the referral hospital in the khuzestan province . inclusion criteria were as follows : healthy women with stable hemodynamic condition and -hcg value of less than 15000 miu / ml . women who had a history of liver and kidney disease , blood dyscrasia or breastfed were excluded from the study ( 14 ) . patients were randomly assigned in two groups of single and double dose by the method of enclosed envelope include block randomization ( with ratio 1:1 ) . according to similar studies , the lowest success rate for single dose and double dose have been reported 55% and 77% , respectively ( 14 ) . considering 95% confidence interval the sample size was calculated as 76 patients ( 38 in each single or double dose group ) according to the following equation : where  = 0.05 and  = 2% . in the single dose group , 50 mg / m mtx was administered at day 0 , while in the double dose group ; patients received two doses of 50 mg / m at days 0 and 4 . the values of -hcg in both groups were measured on the fourth and seventh day of hospitalization . about 15% decrease in -hcg level was considered as a successful treatment . in case of treatment s failure , elective surgery or administration of extra dose of mtx patients remained hospitalized during the intervention period and were checked for the level of -hcg every 48 hours . before prescribing mtx , blood tests , kidney and liver transaminase levels , creatinine and urea levels were measured and if the patients showed any problem , they were excluded from the study . during the intervention , the following signs were compared between two groups and considered as drug complications ; if liver transaminase increased 1.5 times more than normal , or creatinine increased to 1.5 mg / dl , wbc count decreased to 2000 , or platelets declined fewer than 100,000 ( 11 ) . in order to compare the effectiveness of mtx doses in different -hcg levels or mass sizes ; patients were classified in 3 groups of lower than 2000 miu / ml , 2000 - 4000 miu / ml , and more than 4000 miu / ml based on -hcg levels and in 3 groups of lower than 2 cm , 2 - 4 cm and more than 4 cm based on mass size . every woman remained hospitalized under the precise observation until their -hcg value reached 200 miu / ml . the side effects of mtx , as well as function of liver and kidney were checked in each participant one week after completion of treatment and patients were asked for complications such as nausea , vomiting , and gastrointestinal symptoms . the chi - square , independent t test , and logistic regression were used for analyzing data . the normality of data was checked using kolmogorov - smirnov test and as a result , all continuous variables were normal . in the single dose group , 50 mg / m mtx was administered at day 0 , while in the double dose group ; patients received two doses of 50 mg / m at days 0 and 4 . the values of -hcg in both groups were measured on the fourth and seventh day of hospitalization . about 15% decrease in -hcg level was considered as a successful treatment . in case of treatment s failure , elective surgery or administration of extra dose of mtx patients remained hospitalized during the intervention period and were checked for the level of -hcg every 48 hours . before prescribing mtx , blood tests , kidney and liver transaminase levels , creatinine and urea levels were measured and if the patients showed any problem , they were excluded from the study . during the intervention , the following signs were compared between two groups and considered as drug complications ; if liver transaminase increased 1.5 times more than normal , or creatinine increased to 1.5 mg / dl , wbc count decreased to 2000 , or platelets declined fewer than 100,000 ( 11 ) . in order to compare the effectiveness of mtx doses in different -hcg levels or mass sizes ; patients were classified in 3 groups of lower than 2000 miu / ml , 2000 - 4000 miu / ml , and more than 4000 miu / ml based on -hcg levels and in 3 groups of lower than 2 cm , 2 - 4 cm and more than 4 cm based on mass size . every woman remained hospitalized under the precise observation until their -hcg value reached 200 miu / ml . the side effects of mtx , as well as function of liver and kidney were checked in each participant one week after completion of treatment and patients were asked for complications such as nausea , vomiting , and gastrointestinal symptoms . the chi - square , independent t test , and logistic regression were used for analyzing data . the normality of data was checked using kolmogorov - smirnov test and as a result , all continuous variables were normal . sociodemographic characteristics of the patients such as age , parity , and history of abortion are listed in table 1 . as it is evident in table 1 , demographic characteristics and the mean of -hcg level in two groups did not show any significant difference . as demonstrated in table 2 , the success rate of single dose was 69% and in double dose group , it was 79% the rate of operation was 19% and 16% in single and double dose groups , respectively ( p = 0.76 ) . the necessity of extra dose of mtx in the single dose grope was 14% and in the double dose group , it was 6% ( p = 0.23 ) . the two therapeutic methods were compared with regard to 3 different levels of -hcg and mass size . the results of logistic regression showed that there were no any significant differences between two groups in the rate of success considering the level of -hcg and mass size ( p > 0.05 , table 3 ) . results showed that only the rate of operation at the -hcg level of 2000 - 4000 miu / ml was lower in the double dose compared to the single dose group ( p = 0.05 ) . duration of hospitalization in double dose group was significantly lower than that of the single dose group ( 11.55 vs. 14.76 d , p < 0.001 ) . the rate of complications in double dose group was more than single dose group , but no significant difference was observed ( p = 0.32 ) . complications included vomiting and gastrointestinal symptoms and no blood or urine disorders were reported after prescription of mtx among patients . this study designed to compare the effectiveness of single and double doses of mtx in patients with ep . our research showed that double dose method might induce better response with regard to necessity of operation and extra doses of mtx compared to single dose method . therapeutic success of double dose method in our research was 79% , which was lower than hamed et al . study result ( 82% and 88% in the single and double dose , respectively ) ( 13 ) . this discrepancy may be due to the level of -hcg in our patients that was more than that of the hamed et al . they also did not notice any significant relation between therapeutic method and response to the treatment in their research . in a study by barnhart et al . in which they administered 50 mg / m mtx on days 0 and 4 , results showed that the success rate was 87% and the fallopian tubes ruptured in 3% of patients . the reported side effects were mild and transient and most women were satisfied with the treatment ( 14 ) . the rate of success in our study in the double dose group was less than that observed by barnhart et al . study ( 14 ) that may be due the overall level of -hcg in their study which was lower than that of our study . ( 15 ) in a study on 34 patients who received single dose of mtx , noticed the higher rate of success in the group with -hcg level lower than 2000 miu / ml compared to the group with -hcg level more than 4000 miu / ml ( 78% versus 33.33% ) . they concluded that the mean of -hcg is an important factor in response to treatment ( 15 ) . in our study , the rate of success was also higher in the group with -hcg level lower than 2000 miu / ml ( 91.7% and 77% , respectively ) and the mean of -hcg was also lower in patients responded to the treatment than cases who did not .   in a study by alleyassin et al . , they compared the effect of single dose with multiple doses of mtx in selected women . the results showed that the rate of success in the single dose was 88.9% , while in the multiple doses , it was 92.6% ( p > 0.05 ) . the researchers concluded that single dose can be considered as the first choice of treatment in selected patients ( 16 ) . the higher level of initial -hcg in the single dose group in our study may be a reason for this dissimilarity ( 3249  1427 vs. 3146.9  2389 ) . according to our findings , the single dose of methotrexate ( compared to the double dose ) is effective in cases of ep with primary low level of -hcg . however in cases with higher level of -hcg or probability of tube rupture , administration of double dose is recommended . also the duration of hospitalization in the double dose group was significantly lower compared to this time in the single dose group . this is the first time in iran that we compared the single dose versus double dose of mtx for treatment of ectopic pregnancy . results of this study have been considered as a part of treatment regimens in the imam khomeini hospital after completion of this study .