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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 1  |  Page : 250-253

Multiple doses versus single-dose methotrexate protocols for the management of some cases of ectopic pregnancy


Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufiya University, Menoufiya

Date of Submission09-Jul-2014
Date of Acceptance02-Sep-2014
Date of Web Publication29-Apr-2015

Correspondence Address:
Ahmed H Metwalli
3rd Floor, House No 2, Abdel Mohsen Elsabahy Street, Quesna, Menoufiya

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.156003

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  Abstract 

Objective
The aim of the study was to compare the efficacy of two methods of administering methotrexate in the treatment of ectopic pregnancy (EP) - multiple-dose methotrexate intramuscular injection and single-dose methotrexate intramuscular injection - in a prospective randomized study.
Data analysis
Electronic medical research databases were searched from 1982 or from the starting date of each database. The search was performed on 1 March 2013 and included ahead-published printed articles without language restrictions.
Study selection
The initial search presented 250 articles, of which 30 met the inclusion criteria. The articles were previous trials on methotrexate therapy in the treatment of EP as well as current therapies previously trialed and potential therapies for the near future.
Data extraction
Studies that had obtained ethical approval, that followed a prospective randomized design, with specific eligibility criteria, used appropriate controls, and with adequate follow-up and defined outcome measures were selected.
Data synthesis
Although heterogeneity existed in follow-up periods and in reported outcome measures, it was possible to pool the data and perform comparisons by statistical review.
Recent findings
Early diagnosis of EP allows a conservative medical approach with methotrexate, which is considered the treatment of choice over surgical intervention. This includes the use of methotrexate in a single-dose injection or multiple-dose injections as comparable protocols for treatment of EP.
Conclusion
Methotrexate is a reliable method for treatment of early unruptured EP either by single-dose methotrexate intramuscular injection or multiple-dose methotrexate intramuscular injection. There are no significant differences in primary treatment success. Single-dose injections have lower side effects compared with multiple-dose injections.

Keywords: Ectopic pregnancy, intramuscular methotrexate, medical management


How to cite this article:
Elkilani OA, Sayyed TM, Metwalli AH. Multiple doses versus single-dose methotrexate protocols for the management of some cases of ectopic pregnancy. Menoufia Med J 2015;28:250-3

How to cite this URL:
Elkilani OA, Sayyed TM, Metwalli AH. Multiple doses versus single-dose methotrexate protocols for the management of some cases of ectopic pregnancy. Menoufia Med J [serial online] 2015 [cited 2019 Sep 21];28:250-3. Available from: http://www.mmj.eg.net/text.asp?2015/28/1/250/156003


  Introduction Top


Over the past decades, the occurrence of ectopic pregnancy (EP) has been noted all over the world; at present, the rate is nearly 2% of all pregnancies [1]. It is reported to be the major cause of early pregnancy maternal deaths [2]. EP is an important cause of maternal morbidity and occasional mortality. An overall 1.5-2% of all reported pregnancies are extrauterine [3].

Definition of ectopic pregnancy

EPs are those that occur in any location other than the uterus, as shown in [Figure 1] [4]. Black women and women over the age of 35 are reported to be at highest risk [5],[6].
Figure 1: Left tubal ectopic pregnancy on laparoscopy [4].

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Diagnosis of ectopic pregnancy

Quantitative measurements of the b-subunit of human chorionic gonadotropin (b-hCG) and transvaginal ultrasonography have improved the accuracy of diagnosis and allow earlier detection of EPs than was previously possible [7]. Ultrasound remains the modality of choice for the diagnosis of EP. Recognition of the classic presentations of various types of EPs and their complications by ultrasound, and differentiation from other entities that may mimic EP, is crucial to early diagnosis and clinical management [8,9].

Management of ectopic pregnancy

With early diagnosis and treatment, definite therapy for unruptured EP is feasible even before the onset of symptoms [10]. Methotrexate has been used successfully to treat EP. Methotrexate is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase and reduces the supplies of tetrahydrofolate, which is a cofactor in the synthesis of DNA and RNA and necessary for cell division [10],[11].

Methotrexate is currently administered either as a single or as multiple doses to treat EP [12].


  Materials and methods Top


Data analysis

Electronic medical research databases were searched from 1982 or from the starting date of each database. The search was performed on 1 March 2013 and included ahead-published printed articles without language restrictions. All studies were independently assessed for inclusion by two researchers.

Study selection

This randomized study consisted of 40 women with a diagnosis of EP who had been treated with methotrexate. The enrolled participants who had fulfilled the criteria of medical treatment were divided randomly by means of a shuffled randomization approach into two groups. Group A (n = 20) patients had been scheduled for a single dose of methotrexate (1 mg/kg) on day '1' of the treatment. Group B (n = 20) women had been scheduled to receive multiple doses of methotrexate (1 mg/kg) on days 1, 3, 5, and 7, alternating with intramuscular leucovorin rescue factor 0.1 mg/kg of body weight the day after each methotrexate dose. The inclusion criteria had been as follows:

  1. Hemodynamic stability.
  2. Willingness and ability to comply with follow-up.
  3. b-hCG concentration less than or equal to 5000 mIU/ml.
  4. Absence of fetal cardiac activity.
  5. Sac of ectopic smaller than 4 cm.
  6. Normal liver, renal function tests and normal complete blood count.


The initial search presented 250 articles, of which 30 met the inclusion criteria. The articles were previous trials on methotrexate therapy in the treatment of EP as well as current therapies previously trialed and potential therapies for the near future. The article titles and abstracts were initially screened. Then the selected articles were fully read and further assessed for eligibility. All references from the eligible articles were reviewed to identify additional studies. As per recommendations, disagreements between researchers were resolved by consensus. All studies were graded using the criteria for grading studies from the Centre for Evidence Based Medicine.

Data extraction

Studies that obtained ethical approval, had a prospective randomized design, with specific eligibility criteria, that used appropriate controls, and had adequate follow-up and defined outcome measures were selected.

Data synthesis

Although there existed heterogeneity in follow-up periods and in reported outcome measures, it was possible to pool the data and perform comparisons by statistical review.


  Results Top


Forty women with a diagnosis of EP had been treated with methotrexate. Group A (n = 20) patients had been scheduled for a single dose of methotrexate (1 mg/kg) on day'1' of the treatment. Group B (n = 20) women had been scheduled to receive multiple doses of methotrexate (1 mg/kg) on days 1, 3, 5, and 7, alternating with intramuscular leucovorin rescue factor 0.1 mg/kg of body weight the day after each methotrexate dose.

The overall success rate in this study was found to be 92.5%; the success rate in group A was 90% and that in group B was 95%, with significant difference (P = 0.004). Three participants (two in group A and one in group B) had failed response to methotrexate treatment followed by surgical treatment. In group A, the quantitative b-hCG titers of both patient groups on day 7 did not decline more than 15% compared with day 4 of treatment. The third patient in group B had shown signs of disturbed EP and required urgent surgical interference (laparotomy).

In addition, the receiver operator characteristic curve analysis in our study demonstrated that the cutoff level of 3600 mIU/ml for b-hCG level (area under the curve, 0.533) had a sensitivity and specificity of 94.5 and 92.6%, respectively.

There was a statistically significant negative correlation between the pretreatment b-hCG level, the pretreatment ultrasonic detection of endometrial thickness, and the rate of success of the treatment.

In this study, the most common side effect during the course of treatment was found to be gastric upset (60% of patients in group A and 86.7% in group B, insignificant difference). The same observation was made for epigastric and pelvic pain, hair loss, gastric upset, and oral ulcers. The only statistically significant difference was in vomiting (P = 0.020). Another important part of our study was the evaluation of both risk factors as well as the signs and symptoms of presentation for EP. Our study population comprised women who had been admitted with symptoms and signs suggestive of EP, such as pelvic pain (90%), bleeding per vagina (75%), and/or amenorrhea (100%), in the first trimester of pregnancy [Table 1],[Table 2] and [Table 3].
Table 1: Proposal etiologies of ectopic pregnancy [13]

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Table 2: The single-dose protocol of methotrexate in the treatment of early ectopic pregnancy [14]

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Table 3: The multidose protocol of methotrexate in the treatment of early ectopic pregnancy [14]

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  Discussion Top


This prospective randomized study aimed at determining and evaluating two methotrexate regimens (a single-dose regimen and a multiple-dose regimen) for treatment of EP in women who were eligible for medical treatment of EP. This study showed that the multiple-dose regimen of methotrexate therapy (group B) was significantly superior to the single-dose regimen (group A), with an overall success rate of 92.5% for all studied cases. Only three cases had failed in the entire study (two in group A and one in group B) in which surgical interference had been carried out.

In this study, the most common side effect during the course of treatment was found to be gastric upset, constituting 60% in group A and 75% in group B, with insignificant statistical difference. Other side effects such as epigastric and pelvic pain, hair loss, gastric upset, and oral ulcers showed no significant statistical difference. The only statistically significant difference was in vomiting (P = 0.020).

Another important part of this study was the evaluation of both risk factors as well as signs and symptoms of presentation for EP. This study population comprised women who had been admitted with symptoms and signs suggestive of an EP, such as pelvic pain (90%), bleeding per vagina (75%), and/or amenorrhea (100%), in the first trimester of pregnancy.

The receiver operator characteristic curve analysis in our study demonstrated that the cutoff level of 3600 mIU/ml for b-hCG level (area under the curve, 0.533) had a sensitivity and specificity of 94.5 and 92.6%, respectively, for the prediction of treatment success.

There was a statistically significant negative correlation between the preinterference (pretreatment) b-hCG level (≤5000 mIU/ml) and the rate of success of the treatment (P = 0.008), which means that the higher the preinterference b-hCG level, the lower the success rate.

Also there was a statistically significant negative correlation between the pretreatment endometrial thickness detected with ultrasonographic scanning (if >12 mm) and the overall success rate (P = 0.05).

A limitation of our study was the small sample size. In turn, the power of our study was not large enough to detect small differences in the comparable parameters between the two methods of treatment.


  Conclusion Top


Methotrexate therapy is a safe and effective alternative for the management of undisturbed EP with mild side effects and with the associated advantage of avoiding invasive surgery, provided the criteria of medical management are strictly fulfilled. A multiple-dose regimen of methotrexate is more effective in the treatment of EP compared with a single-dose regimen.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.[22]

 
  References Top

1.
Guvendag Guven ES, Dilbaz S, Dilbaz B, et al. Comparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study. Acta Obstet Gynecol Scand 2010; 89 :889-895.  Back to cited text no. 1
    
2.
Casikar I, Reid S, Condous G. Ectopic pregnancy: ultrasound diagnosis in modern management. Clin Obstet Gynecol 2012; 55 :402-409.  Back to cited text no. 2
    
3.
Coste J, Bouyer J, Job-Spira N. Epidemiology of ectopic pregnancy: incidence and risk factors. Contracept Fertil Sex 1996; 24 :135-139.  Back to cited text no. 3
    
4.
Sivalingam VN, Duncan WC, E Kirk, et al. Simpson Centre for Reproductive EH16 4SA. J Fam Plann Reprod Health Care 2011; 37 :231-240.  Back to cited text no. 4
    
5.
Goldner TE, Lawson H, Xia Z. Surveillance for ectopic pregnancy-United States, 1970-1989. MMWR CDC Surveill Summ 1993; 42 :73-85.  Back to cited text no. 5
    
6.
Ness RB, Mclaughlin MT, Heine RP, et al. Fetal fibronectin as a marker to discriminate between ectopic and intrauterine pregnancies. Am J Obstet Gynecol 1998; 179:697.  Back to cited text no. 6
    
7.
ACOG practice. Medical management of tubal pregnancy. Clinical management guidelines for obstetrician-gynecologists. Washington, DC: American College of Obstetrician and Gynecologists; 1998.  Back to cited text no. 7
    
8.
Cerveira I, Costa C, Santos F, et al. Cervical ectopic pregnancy successfully treated with local methotrexate injection. Fertil Sertil 2008; 90 (5).  Back to cited text no. 8
    
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Eskandar M. Single dose methotrexate for treatment of ectopic pregnancy: risk factors for treatment failure. Middle East Fertil Soc J 2007; 12 :57-62.  Back to cited text no. 10
    
11.
Gervaise A, Fernandez H. Methotrexate administration in the treatment of unruptured tubal pregnancy. Prospective non-randomized study: intramuscular injection versus transvaginal sonography-guided injection. J Gynecol Obstet Biol Reprod (Paris) 2003; 32 :420-425.  Back to cited text no. 11
    
12.
Cunningham F, Leveno K, Bloom S, et al. In:: Hauth J, Gilstrep L, Wenstrom Keds. Ectopic pregnancy. Williams obstetrics. 22nd ed. New York: McGraw-Hill; 2005. 253-272.  Back to cited text no. 12
    
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Russell JB. The etiology of ectopic pregnancy. Clin Obstet Gynecol 1987; 30 :181.  Back to cited text no. 13
    
14.
Committee of American Society for Reproductive Medicine. Appropiate use of medical therapy of early ectopic pregnancies is discussed. Fertil Steril 2008; 90 :S206-S212.  Back to cited text no. 14
    
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Saunders BA, Stovall TG. Ectopic pregnancy Clinical gynecology. 1st ed.. Philadelphia, PA: Churchill Livingstone Elsevier; 2006. 205-217.  Back to cited text no. 15
    
16.
Ory SJ, Nnadi E, Melton LJ. Fertility after ectopic pregnancy. Fertil Sertil 1993; 60 :231-235.  Back to cited text no. 16
    
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Cates W, Rolfs RT, Aral So. Sexually transmitted diseases, pelvic inflammatory disease. Epidimol Rev 1999; 12 :215-220.  Back to cited text no. 17
    
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Farquhar CM. Ectopic pregnancy. Lancet 2005; 366 :583-591.  Back to cited text no. 18
    
19.
Franks AL, Beral V, Hogue CJ, et al. Contraception and ectopic pregnancy risk. Am J Obstet Gynecol 1990; 1634 :11120-11123.  Back to cited text no. 19
    
20.
Gungorduk K, O Asicioglu, G Yildirim, et al. Comparison of single-dose and two-dose methotrexate protocols for the treatment of unruptured ectopic pregnancy. J Obstet Gynecol 2011; 31 :330-334.  Back to cited text no. 20
    
21.
Hajenius PJ, Mol BWJ, Bossy PMM, et al. Intervention for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007.  Back to cited text no. 21
    
22.
Potter MB, Lepine LA, Jamieson DJ. Prediction of success with methotrexate treatment of tubal ectopic pregnancy at Grady memorial Hospital. Am J Obstet Gynecol 2003; 18:1192-1194.  Back to cited text no. 22
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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