Archives of Academic Emergency Medicine. 2020; 8 (1): e9 REV I EW ART I C L E Creatine phosphokinase, a new marker in diagnosis of tubal ectopic pregnancy; A Systematic Review Maryam Ghorbani1, Afsaneh Keramat2∗, Farideh Mohsenzadeh Ledari3 1. Student Research Committee, School of Nursing and Midwifery, Shahroud University of Medical Sciences, Shahroud, Iran. 2. Reproductive Studies and Women’s Health Research Center, Shahroud University of Medical Sciences, Shahroud, Iran. 3. Infertility and Health Reproductive Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. Received: October 2019; Accepted: December 2019; Published online: 11 January 2020 Abstract: Introduction: Creatine phosphokinase (CPK) is an intracellular enzyme found in higher levels in the brain, my- ocardium, soft muscle and skeletal muscle, as well as the fallopian tube. This review was conducted to evaluate the role of serum CPK in early diagnosis of tubal ectopic pregnancy (EP). Methods: We performed an elec- tronic literature search in Web of Science, Scopus, Embase and Medline databases and manual search in Google scholar and evaluated papers from the beginning of 1990 to September 2018. The inclusion criteria consisted of cohort, case-control and diagnostic value studies in English or Persian. Two independent researchers used the inclusion and exclusion criteria. In cases where there was doubt about the eligibility of studies, this problem was resolved by consulting a third researcher. After a thorough search, finally, we found 27 papers. However, four of these articles did not have the inclusion criteria and we excluded them from the study. As a result, 24 studies were evaluated. Results: Most studies have approved the use of CPK measurements in EP diagnosis. The main variable measured in most studies was the mean total CPK level. However, there is limited knowledge about the efficacy of measuring CPK levels in EP diagnosis; this review of studies shows positive results regarding use of CPK in EP diagnosis. Conclusions: The results highlighted the potential benefits of CPK as a marker for early diagnosis of EP. Keywords: Pregnancy, ectopic; early diagnosis; creatine kinase; biomarkers Cite this article as: Ghorbani M, Keramat A, Mohsenzadeh Ledari F. Creatine phosphokinase, a new marker in diagnosis of tubal ectopic pregnancy; A Systematic Review. Arch Acad Emerg Med. 2020; 8(1): e9. 1. Introduction Ectopic pregnancy (EP) occurs when a blastocyst abnormally implants outside the endometrium of the uterus (1). It im- plants in the fallopian tube in more than 95% of cases (2). This disorder is a major health problem worldwide (3). The prevalence of EP has doubled since 1960 and accounts for about 2% of the pregnancies in the first trimester (1). In re- cent years, its incidence has increased due to the increase in incidence of pelvic inflammatory diseases, use of fertil- ity drugs, and pelvic surgery (2). Although maternal mor- tality due to ectopic pregnancy has decreased recently, it is still one of the leading causes of death in the first trimester of pregnancy; hence, early management of ectopic pregnancy ∗Corresponding Author: Afsaneh Keramat; 7tir Street, Shahroud University of Medical Sciences, Shahroud, Iran. Tel: 00989125498075, E-mail: kera- mat2222@gmail.com is very important (3). In developing countries, such as Iran, 10% of women diagnosed with ectopic pregnancy do not sur- vive because they refer to the hospital very late (1). Clinical manifestations in ectopic pregnancy can be simi- lar to other conditions. This reveals the need to search for some new diagnostic tools. Transvaginal ultrasound and se- rial measurement of serum beta-hCG levels are the most common diagnostic methods for EP (4). Despite the use of transvaginal ultrasound and measurement of beta-hCG lev- els, about 40% to 50% of the initial cases of the disease are not diagnosed. Transvaginal ultrasonography can help if there is an intrauterine pregnancy or an adnexal mass, and mea- surement of serum beta-hCG levels can detect a normal in- trauterine pregnancy from a nonviable pregnancy, but it can- not differentiate an intrauterine pregnancy that has stopped growing from an ectopic pregnancy (5). Creatine phosphok- inase (CPK) was proposed as a new EP diagnostic criterion. Lavie et al. were the first to report a sensitivity and speci- ficity for overall CPK levels in detecting EP (2). CPK is an in- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 2 tracellular enzyme found in higher levels in the brain, my- ocardium, soft muscle and skeletal muscle, as well as the fal- lopian tube (4). CPK has three definite Isozymes, including CPK-MM, MB, and BB. Due to the lack of a submucosal layer in the fallopian tube, the zygote implants are placed adjacent to the muscle layer in tubal ectopic pregnancy, and this inva- sion leads to an increase in the level of CPK as a soft muscle damage marker (2). Due to the need for and importance of early detection and timely treatment of EP and the ambiguousness of ultrasound in most patients, this review is conducted to evaluate the role of serum CPK in early diagnosis of tubal ectopic pregnancy. 2. Methods: In this systematic review, researchers performed an elec- tronic search using the keywords of Tubal pregnancy, Ec- topic pregnancy, EP, Creatinine phosphokinase, and CPK in Medline (via PubMed), Embase, Web of Science, and Scopus databases. Manual search was also performed in Google scholar to find relevant papers. We included ar- ticles published from the beginning of 1990 to September 2018. Search terms were selected based on common key- words in literature. The keywords were combined using (AND) and (OR) operators. We used the following search strategy for finding articles with related titles and abstracts in PubMed: ((("Creatine Kinase"[Mesh] OR "Creatine Kinase, MB Form"[Mesh]) AND "Pregnancy, Tubal"[Mesh]) AND "Pregnancy, Ectopic"[Mesh]) AND ("1980/01/01"[PDAT]: "2018/12/31"[PDAT]). 2.1. Search strategy The inclusion criteria consisted of cohort, case-control and diagnostic accuracy studies in English or Persian. Exclusion criteria consisted of articles in languages other than English and Persian, and lack of reporting the data necessary for the study. 2.2. Quality control of the study Two independent researchers searched the articles in accor- dance with inclusion and exclusion criteria. In cases where there was disagreement about the eligibility of studies, we solved the problem by consulting a third researcher. As a re- sult, this review used 24 studies to evaluate the value of CPK in diagnosis of EP. This systematic review was reported according to PRISMA checklist criteria. The methodological elements of the study, including data extraction, proper sampling descrip- tion, study design, participants’ characteristics, and inclu- sion and exclusion criteria were evaluated to ensure the qual- ity of the selected papers. Two researchers searched and ex- tracted data independently. QUADAS-2 checklist was used Figure 1: PRISMA flow diagram of the study selection process. for controlling the selected studies. This tool comprises four domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first three domains are also assessed in terms of concerns regarding applicability. Signaling questions are included to help judge risk of bias. 3. Results After a thorough search, we found 27 papers on CPK as a marker in diagnosis of tubal EP. However, three of these ar- ticles did not meet the inclusion criteria and we excluded them from the study for reasons including failure to report the complete information for the study, type of study, and the language of the study. As a result, 24 studies (2, 4, 6-27) were used to evaluate the value of CPK in diagnosis of EP (Figure 1). 3.1. Quality assessment of studies and risk of bias The risk of bias in index test, flow and timing and reference standard were low in most studies (83.3% to 91.66% of arti- cles), but in patient selection, 29.11% of articles were high risk, 4.16% of them had unclear risk, and 66.66% had low risk. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Figure 2: Risk of bias and applicability graph. There were no high applicability concerns regarding patient selection, index test and reference standard among articles. Figure 2 and 3 show the result of quality assessment of stud- ies. Table 1 shows the general characteristics and data of each of the articles that were included in the study. Total sample size in these 24 articles was 2180 cases in dif- ferent groups of patients. In all of them the control groups were normal/ intrauterine pregnancy or non-Ep groups and in most of them there was also a third control group, which was abortion cases (2, 4, 9-17, 19, 21, 22, 26, 27). In a study by Chandra & Jain in 1995, two other control groups were also included; acute appendicitis and pelvic inflammatory dis- ease. The result of this study showed significant difference in CPK level of EP group and these groups of patients (11). Most studies have approved the use of serum CPK measurement in EP diagnosis and showed significant difference between ectopic pregnancies and intrauterine pregnancies (2, 4, 6, 7, 9-11, 16, 18, 19, 22-27) but six studies did not show any signif- icant difference (8, 12-15, 17) . The main variable measured in most studies was the mean total CPK level, which had a wide range in these articles; ranging from 33.4 to 185.6 IU/L (Table 1). Reference tests for confirming ectopic pregnancy in almost all of studies were B-hCG blood sampling and/or ultrasonography. Mean reported level of CPK was 95.02±51.09 IU/L for ectopic pregnancies and 53.61±19.15 IU/L for normal/intrauterine pregnancies in studies that used the same unit for reporting this biomarker (2, 4, 6, 7, 9-13, 15-18, 22-24, 27). A few studies reported the area under the receiver operating characteristic (ROC) curve of CPK in this regard; Birkhahn et al. (21): 0.56, Ghahiri et al. (25): 0.692, Soundravally et al. (4): 0.851, and Shafi et al. (7): 0.864. According to these reported results, mean area under the ROC curve of CPK was 0.72 in diagnos- ing ectopic pregnancies. Studies reported different cut-points for level of CPK in diag- nosis of ectopic pregnancy, ranging from 26.5 to more than 145 IU/ with sensitivity and specificity ranging from 65% to 95% and 64.5% to 100%, respectively (2,4, 6,11, 12, 16-19, 24-28). For example, Lavie et al. (9), reported CPK level of 45 IU/L as a cut-point for diagnosing EP with 100% sensi- tivity and 100% specificity, whereas at the same cut-point, Duncan et al. (10) and Zorn et al. (15) reported sensitiv- ity of 57% and 50%, and specificity of 67% and 76%, respec- tively. Some studies, only reported the cut-point without cal- culating sensitivity and specificity; for example Korhonen et al. (14), Plewa et al. (16), and Vitoratos (17), claimed that CPK=30 IU/L, CPK âL’ě 74 IU/L, CPK=145 IU/L are suitable for diagnosing ectopic pregnancy, respectively. 4. Discussion The results highlighted the potential benefits of CPK as a marker for early diagnosis of EP. Studies show that the re- ported prevalence of EP is increasing in different countries in recent decades due to improved initial diagnosis and in- creased risk factors for EP, especially the use of assisted repro- ductive technology. Timely diagnosis of EP saves the mother and ensures her health. Therefore, we conducted a system- atic review of existing papers to investigate and introduce an applied method for early diagnosis of EP to prevent its com- plications and consequences. CPK is an intracellular enzyme in muscle cells and its plasma level increases in cell lysis. Lysis of trophoblast cells leads to an increase in plasma CPK levels. Therefore, the level of this enzyme can be used for evaluation of tubal ectopic preg- nancy because increased CPK can be associated with tro- phoblastic invasion and trophoblast mass (6). Currently, transvaginal ultrasound and serial measurement of serum beta-hCG levels are the most common diagnostic methods for ectopic pregnancy (7). If the ultrasound shows the presence of pregnancy tissue in adnexa without evidence of intrauterine pregnancy, the presence of ectopic pregnancy should be suspected (28), If the yolk sac or embryo are de- tected in the EP tissue, the diagnosis of EP is confirmed. Serum beta-hCG also plays an important role in diagnosis of EP along with ultrasound (29). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 4 Figure 3: Risk of bias and applicability concerns summary. Despite the widespread use of transvaginal ultrasound and beta-hCG, it is believed that 40% to 50% of EP cases remain unidentified in the early stages. Despite the advances in ul- trasound, according to recent reports, 48-8% of all patients with abdominal pain or vaginal bleeding in the first trimester of pregnancy have an uncertain ultrasonography with serum beta-hCG level less than 1000 IU/dl. Particularly, this sub- group of patients are not properly evaluated and may bene- fit most from other serum markers that allow rapid diagnosis (7). According to the present review, researchers around the world are interested in using CPK as a diagnostic marker for early detection of EP. Asgharnia et al. reported that determin- ing the total CPK level could increase its diagnostic value in diagnosis of tubal ectopic pregnancy; however, the need for larger scale studies was felt to appropriately determine the cut-off point of this marker. They did not find any significant differences between study groups regarding CPK-MB levels (2). Six of the papers reviewed in this study did not confirm the significance of the differences in CPK levels between those with intrauterine and ectopic pregnancies. According to the studies summarized in Table 1, all of these articles, except for one published in 2012 (8), were published in the years be- fore 2000 (12-17). Kruchkovich et al. reported that no signif- icant difference in CPK and CPK-MB levels had a diagnostic value for EP. They concluded that the inaccuracies observed regarding CPK in that study could be due to the participa- tion of subjects with less than 7 weeks of gestational age be- cause CPK level might also be related to the gestational age (8). Plewa et al. reported that although there are higher levels of CPK in patients with ectopic pregnancy compared to those with abortion or normal pregnancy, due to a significant over- lap in CPK levels, the use of this serum marker for EP diagno- sis is unreliable (16). A drawback of that study was its small sample size, especially in the EP group, which can reduce the confidence in the confirmation of its findings. 4.1. The strengths and limitations of this study • This study examined various aspects of CPK and its evi- dence in early diagnosis of EP. • Systematic reviews provide the highest level of evidence for decision-making. To the best of our knowledge, there was no systematic review for the current issue. • Two independent researchers conducted screening and ex- traction of studies. 5. Conclusion According to this review, serum CPK level can be used as a diagnostic marker for ectopic pregnancies and it seems that mean level of CPK is 95.02±51.09 IU/L for ectopic pregnan- cies and 53.61±19.15 IU/L for normal/intrauterine pregnan- cies. 6. Declarations: 6.1. Acknowledgements The authors thank Shahroud University of Medical Sciences for its financial support. 6.2. Authors Contributions Maryam Ghorbani developed the original idea and the pro- tocol, searched in different scientific websites, abstracted and analyzed data, assessed quality of articles, wrote the This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 manuscript and prepared the table. Afsaneh Keramat contributed to the development of the pro- tocol, abstracted data, searched in different scientific web- sites and prepared the manuscript, assessed quality of arti- cles and is guarantor. Farideh Mohsenzadeh Ledari assessed quality of articles, edited grammatical and translation errors. Authors ORCIDs Maryam Ghorbani: 0000-0003-3946-7479 Afsaneh Keramat: 0000-0002-8728-7790 Farideh Mohsenzadeh Ledari: 0000-0001-8939-3186 6.3. Funding Support This research was financially supported by Shahroud Univer- sity of Medical Sciences. 6.4. Conflict of Interest Authors declare that there is no conflict of interest. References 1. Saadati N, Najafian M, Masihi S, Safiary S, Abedi P. Com- parison of two different protocols of methotrexate ther- apy in medical management of ectopic pregnancy. Ira- nian Red Crescent Medical Journal. 2015;17(12). 2. Asgharnia M, Faraji R, Mirblouk F, Roshan ZA, Parvizi A. Evaluation of serum creatine phosphokinase in diagno- sis of tubal ectopic pregnancy compared with intrauter- ine pregnancy and threatened abortion. Iranian journal of reproductive medicine. 2012;10(4):303. 3. Ghelichkhani P, Yousefifard M, Nazemi L, Safari S, Hos- seini M, Baikpour M, et al. The value of serum Κ- subunit of human chorionic gonadotropin level in pre- diction of treatment response to methotrexate in man- agement of ectopic pregnancy; a systematic review and meta-analysis. 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Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 1 Lavie et al. (9)1993 Mean age of participants: Not reported Mean gestational age: Not reported Total sample size: 51 Groups of study: 3 groups of women: Tubal pregnancy (n=17) Missed abortion (n=17) Normal pregnancy (n=17) Method of measuring CPK: Reflectance spectropho- tometry of chromophore production. Time of sampling: On admission Reference test to confirm ectopic pregnancy: Physical examination, ultrasonographic exami- nation, and routine blood tests Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 78.125 ± 6.369 Mean level(±SD) of CPK in intra uterine pregnancies(IU/l): 31.125 ± 2.213 Mean level(±SD) of CPK in missed abortions(IU/L): 26 .25 ± 6.149 p-value: p < 0.0001 (Sig1 ) Cut-point 45 IU/L Sensitivity: 100% Specificity: 100% 2 Duncan et al. (10) 1995 Mean age of participants: Not reported Mean gestational age: Not reported Total sample size: 120 Groups of study: 4 groups of patient: EP (n=21), complete miscar- riage (n=47), incomplete miscarriage (n=32), ongo- ing pregnancies (n=20). Method of measuring CPK: Hitachi discrete analyzer Time of sampling: on admission Reference test to confirm ectopic pregnancy: Initial clinical assessment and plasma hCG concen- tration, laparoscopy or la- parotomy, histological as- sessment. Mean level of CPK in Intact Ectopic pregnancy(IU/l): 53.4 Mean level of CPK in complete miscarriage: 37.7 Mean level of CPK in intra uterine pregnancy(IU/l): 42 P –value: P < 0.001 (Sig) Cut-point: 45 IU/L Sensitivity : 0.57 Specificity : 0.67 3 Chandra & Jain (11) 1995 Mean age of participants: Not reported Mean gestational age: 6-8 weeks Total sample size: 90 Groups of study: 5 groups of patients; Nor- mal pregnancy (n=20), Missed abortion(n=20), Tubal pregnancy (n=20), Acute appendicitis (n=10) Pelvic inflammatory dis- ease (n=20). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 8 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 3 Method of measuring CPK: Beckman CX- 5 Synchron (Brea, CA) fully automated clinical chemistry analyzer. Time of sampling: before any surgical intervention Reference test to confirm ectopic pregnancy: Physical examinations were car- ried out along with routine blood tests and ultrasonographic examination. Mean level (±SD) of CPK in Intact Ectopic pregnancy(IU/l): 126±51.78 Mean level(±SD) of CPK in missed abortion: 41±9.7 Mean level(±SD) of CPK in pelvic inflammatory disease: 46±9.7 Mean level(±SD) of CPK in acute appendicitis: 52±14.38 Mean level(±SD) of CPK in normal pregnancy: 42±9.34 P-value: P < 0.0001, (Sig). 4 Darai et al. (12) 1996 Mean age of participants: Not reported Mean gestational age in EP: 47.6 days Mean gestational age in ongoing pregnancy: 49.3 days Mean gestational age in missed abortion: 48.7 days No statistically significant difference in GA was found between the 3 groups. Total sample size: 90 Groups of study: 3 groups of women: Tubal pregnancy (n=30) Ongoing pregnancy(n=30), spontaneous Miscarriage(n=30) Method of measuring CPK: multiparametric analyser (Hi- tachi 737) with CK N- acetyl cysteine reagents (Boehringer Mannheim UK Ltd, Leves, UK) Time of sampling: before any surgical intervention Reference test to confirm ectopic pregnancy: progesterone, beta-hCG, pelvic sonography Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 81.4±66.2 IU/L Mean level(±SD) in missed abortions (IU/L): 84.8±49.3 Mean level(±SD) of CPK in ongoing pregnancies(IU/l): 81.5±40.3 p-value: Not reported There was no statistically signifi- cant difference in these 3 groups. (NS2 ) There was no significant differ- ence in CK level between pa- tients with rupture of tubal wall and patients without rupture. (NS) There was not any difference in CKMB level between 3 groups of patients. (NS) 5 Lincoln et al. (13) 1996 Mean age of participants: Not reported Mean gestational age: First-trimester Total sample size: 51 Groups of study: 3 groups of patients: sponta- neous abortion (n=16), EP (n=18) ongoing pregnancy (n=17) This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 5 Lincoln et al. (13) 1996 Method of measuring CPK: Ektachem 700 discrete analyzer (Eastman Kodak Co., Rochester, NY). Time of sampling: on admission Reference test to confirm ectopic pregnancy: Quantitative hCG level, transvagi- nal sonography and surgery. Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 90.6±15.9 Mean level(±SD)of CPK in ongoing pregnancies(IU/l): 78±13.8 Mean level(±SD)of CPK in abortions(IU/l): 94.1±13 p-value: p>0.7 (NS) AUC3 : 0.501 ± 0.007. p-value: P > 0.05, (NS). 6 Korhonen et al. (14) 1996 Mean age of participants: Not reported Mean gestational age in EP group: 44.9 ± 9.9 days Mean gestational age in normal pregnancy group; 37.5 ± 4.0 Total sample size: 44 Method of measuring CPK: Hitachi 911 discrete ana- lyzer using CK N-acetyl cys- teine activation reagents at 37◦C Time of sampling: On admission or after repeated ex- aminations Groups of study: 3 groups of patients: Sponta- neous abortion, blighted ovum, or Missed abor- tion (n=15) Tubal pregnancy (n=15) Normal in- trauterine preg- nancy (n=14). Reference test to confirm ectopic pregnancy: Transvaginal sonography, la- paroscopy and serum hCG Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): Not reported Mean level (±SD) of CPK in intra uterine pregnancies(IU/l): Not reported Mean level (±SD) of CPK in missed abortions(IU/l): Not reported p-value: Not reported No significant differences in CK levels were ob- served between the groups. (NS) Cut-point: 30 IU/L p-value: P < 0.005, (Sig.) Sensitivity: Not reported Specificity: Not reported This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 10 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 7 Zorn et al. (15) 1997 Mean age of participants: Not reported Mean gestational age: Not reported Total sample size: 57 Groups of study: 3 groups of pa- tients: normal pregnancy (n=20), miscarriage (n=23), EP (n=14). Method of measuring CPK: Hitachi 717 ana- lyzer Time of sampling: On admission Reference test to confirm ectopic pregnancy: B-hCG Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 44.2±3.6 Mean level(±SD) of CPK in intra uterine pregnancies(IU/l): 36.8±5.1 Mean level(±SD) of CPK in intra miscarriages(IU/l): 51.7±7.2 p-value: Not reported There was no significant dif- ference between either normals and miscarriages or miscarriages and ectopics. Cut-point: > 45 IU/L p-value: P < 0.02 (Sig) Sensitivity: 0.50 Specificity: 0.76 PPV: 0.69 8 Plewa et al. (16) 1998 Mean age of participants: Not reported Mean gestational age in participants: 7.3± 2.3 weeks Total sample size: 64 Groups of study: 3 groups of pa- tients: EP (n=15) Threatened mis- carriage (n=28) Normal pregnancy (n=21). Method of sampling CPK: CK was spec- trophotometrically assayed with stan- dard reagents by an enzymatic rate method on a Syn- chron CX System Time of sampling: Initial presentation Reference test to confirm ectopic pregnancy: quantitative beta- hCG Laparoscopy, ultrasonography, dilatation and curettage Mean level (±SD) of CPK in Intact Ectopic pregnancy(IU/l): 88.8±33.6 Mean level (±SD) of CPK in intra uterine pregnancy(IU/l): 56±38.1 Mean level (±SD) of CPK threatened miscarriage (IU/l): 65.9±59 p-value: p=0.02, (Sig) Cut-point. ≥ 74 IU/L Sensitivity: Not reported Specificity: Not reported This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 11 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 9 Vitoratos et al. (17) 1998 Mean age of participants: Not reported Mean gestational age: Not reported Total sample size: 66 Groups of study: 3 groups of patients; EP (n=21), Normal preg- nancies (n=20), Abortion (n=15). Method of measuring CPK: Not reported Time of sampling: Not reported Reference test to confirm ectopic pregnancy: beta-hCG, sonography Mean level (±SD) of CPK in asymptomatic Ectopic pregnancies(U/l): 58.5 ± 12.42 Mean level (±SD)of CPK in symptomatic Ectopic pregnancies(U/l): 59 ±10.08 p-value: p = 0.45, (NS) 1.Mean level (±SD) of CPK in normal pregnancies (U/l): 58.5 ± 7.24 2.Mean level (±SD) of CPK in threatened abortion (U/l): 73 ± 11.43 Cut-point: 145 IU/l Sensitivity: Not reported Specificity: Not reported 10 Saha et al. (18) 1999 Mean age of participants: Not reported Mean gestational age: Not reported Total sample size: 40 Groups of study: 2 groups of patients: EP (n=20), Normal preg- nancy (n=20). Method of sampling CPK: Kontron-890 spec- trophotometer Time of sampling: before any invasive pro- cedure Reference test to confirm ectopic pregnancy: Physical examination, routine blood test, ultrasonographic ex- amination and urine pregnancy test. Mean level (±SD) of CPK in Intact Ectopic pregnancy(IU/l): 34.15± 1.17 Mean level (±SD) of CPK in intra uterine pregnancy(IU/l): 18.72 ± 1.25 p-value: p< 0.001, (Sig) Cut-point: Not-reported sensitivity: Not reported specificity: Not reported 11 Spitzer et al. (19) 2000 Mean age of participants: Not reported Mean gestational age: First trimester Total sample size: 65 Groups of study: 3 groups of patients: EP (n=23), Normal preg- nancy (n=21), Abnormal pregnancy (n=21). Method of sampling CPK: Hitachi discrete analyzer using creatine ki-nase N- acetyl cysteine activation reagents at 37 Time of sampling: On admission Reference test to confirm ectopic pregnancy: Transvaginal ultrasound examination and blood sample for evaluat- ing progesterone, 17- hydroxyprogesterone, CA-125 and androstene- dione This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 12 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 11 Spitzer et al. (19) 2000 Mean age of participants: Not reported Result in patients with 45days of amenorrhea: Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 88.6/96.3± 37.4 Mean level (±SD) of CPK in normal pregnancies(IU/l): 54/54.1 ± 170 Mean level (±SD) of CPK in abnormal pregnancies(IU/l): 77/78.1 ± 46.4 p-value: p < 0.002 Result in patients With 2500 MIU/ML B-hCG: Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 84.5/88.1± 31.8 Mean level (±SD) of CPK in normal pregnancies(IU/l): 30.6 Mean level (±SD) of CPK in abnormal pregnancies(IU/l): 61/62.5± 24.7 Cut-point: P>0.50 IU/L Sensitivity: 94% Specificity: 31% Cut-point: P>0.70 IU/L Sensitivity : 78% Specificity: 81% 12 Birkhahn* et al. (20) 2000 Mean age of participants in non EP group: 29.4±6.1 *In this article different unit (mIU/dl) Mean gestational age: First trimester has been used for measuring CPK Mean age of participants in EP group: 31.2±5.8 Total sample size: 42 Groups of study: 2 groups of patients: EP (n=21), Non-EP (n=21). Method of measuring CPK: Not reported Time of sampling: At the time of presen- tation Reference test to confirm ectopic pregnancy: Ultrasonography, laparoscopy, or la- parotomy. Mean level (±SD) of CPK in Intact Ectopic pregnancies (mIU/dl): 118±47 Mean level (±SD) of CPK in nonEps (mIU/dl): 64±45.3 p-value: P < .0031, (Sig) Cut-point: 70 mIU/dL Sensitivity: 100% Specificity: 61.9% PPV: 72.4% NPV: 100% 13 Birkhahn* et al. (21) 2001 Mean age of participants in EP group: 31.9 *In this article different unit (ng/dl) Mean age of participants in non-EP group: 27.8 has been used for measuring of CPK Mean gestational age: First trimester Total sample size: 378 Groups of study: 2 groups of patients: patients at less than 5 weeks’ gestation and EP(n=61: ruptured=24 or unruptured=37), non-ectopic preg- nancy(n=317; spon- taneous abortion, threatened, incom- plete, missed, and complete, urinary tract infection, corpus luteal cyst, nonspe- cific abdominal pain, renal cyst, pelvic in- flammatory disease, or appendicitis ). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 13 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 13 Method of measuring CPK: OPERA, Bayer Corpo- ration, Pittsburgh, PA Time of sampling: At the time of presen- tation Reference test to confirm ectopic pregnancy: Surgical pathology reports or ultrasono- graphic scans, β-hCG, SMHC4 and myo- globin test. Mean level (95% CI) of CPK in Ectopic pregnancies (ng/dl): 119 (89–149) Mean level (95% CI) of CPK in unruptured Ectopic pregnancies (ng/dl): 104 (85–122) Mean level (95% CI) of CPK in ruptured Ectopic pregnancies (ng/dl): 139 (66–212) Mean level (95% CI) of CPK in non-Ectopic pregnancies (ng/dl): 105 (95–115) p-value: Not reported The AUC for total creatine kinase: 0.56 (95% CI0.51 to 0.61) Cut-point: 1.1 µg/L Sensitivity: 72% Specificity: 52% The AUC for SMHC: 0.63 14 Develioglu et al. (6) 2002 Mean age of participants in isthmic EP group: 34±3.3 Mean age of participants in ampullary EP group: 31.5±5.1 Mean gestational age in isthmic EP: 35.8±3.7 days Mean gestational age in ampullary EP: 37.6±5 days Total sample size: 52 Groups of study: 2 groups of patients: EP (n=32), Intrauter- ine pregnancies (n=20). Method of measuring CPK: spectrophotometric method on a Tech- nicon DAX Systems automated analyzer Time of sampling: On admission Reference test: beta-hCG, ultrasound, endometrial biopsy, laparoscopy or laparo- tomy. Mean level (±SD) of CPK in in isthmic EP(IU/l): 185.6±58.3 Mean level (±SD) of CPK in in ampullary EP(IU/l): 112.3±55.5 p-value: P=0.011, (Sig) Mean level (±SD) of CPK in in ruptured EP(IU/l): 152.1±61.2 Mean level (±SD) of CPK in in unruptured EP(IU/l): 91.6±44.3 Mean CK level in normal pregnancy (IU/l): 77.4±38.2 p-value: P<0.011, (Sig) Com- paring CPK levels in isthmic and ampullary ectopic pregnancies. P<0.003, (Sig) Com- paring CPK levels in ruptured ectopic preg- nancy and unruptured P<0.0001, (Sig). Com- paring CPK levels in unruptured ectopic pregnancy and normal pregnancy. Cut-point: >120 Iu/L Sensitivity: 65% Specificity: 87% This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 14 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 15 Katsikis et al. (22) 2006 Mean age of participants in EP group: 28.1±6.3 Mean age of participants in abortion group: 26.9±4.9 Mean age of participants in normal pregnancy: 24.6±2.7 Mean gestational age: First trimester Total sample size: 80 Groups of study: 3 groups of patients: EP (n=40), Abortion (n=20), Normal intrauterine preg- nancy (n=20). Method of measuring CPK: enzyme-linked im- munoassay (ELISA) Time of sampling: at the time of presentation and 24 hours after surgery in the subgroups of women with EP and Intra uterine abortion Reference test to confirm ectopic pregnancy: Clinical assessment and transvaginal ultrasonogra- phy, beta-hCG Mean level (±SD) of CPK in Ectopic pregnancies (U/l): 33.4±15.4 Mean level (±SD)of CPK in normal pregnancies (U/l): 24.7±5.7 Mean level (±SD)of CPK in abortions (U/l): 17.9±3.7 p-value of comparing CPK in EP with both IU abortions: p<0.001, (Sig). p-value of comparing CPK in EP with normal gestations: p<0.01, (Sig). p-value of comparing CPK-MB in normal p<0.01, (Sig). pregnancy compared with EP or IU abortion: Cut-point: >26.5 U/L Sensitivity: 80% Specificity: 87.5% PPV: 86.5% NPV: 81.4% Cut-point: < 14.4 U/L Sensitivity: 82.5% Specificity: 95% PPV: 94.3% NPV: 84% 16 Wazir et al. (23) 2009 Mean age of participants: Not reported Mean gestational age: First trimester Total sample size: 100 Groups of study: 2 groups of patients: Tubal pregnancy (n=50), Intra uterine pregnancy (n=50). Method of measuring CPK: Not reported Time of sampling: On admission Reference test to confirm ectopic pregnancy: physical examination, routine investigations and ultrasonography of abdomen, transvaginal ultrasound, laparoscopy and/ or laparotomy Mean level (±SD) of CPK in Ectopic pregnancies(IU/l): 103±50 Mean level (±SD) of CPK in normal pregnancies(IU/l): 52.4 ±10.9 p-value: P=0.000, (Sig). Mean level (±SD) of CPK in ruptured Ectopic pregnancies(IU/l): 119.8±70.5 Mean level (±SD) of CPK in unruptured Ectopic pregnancies(IU/l): 88.6±19.6 P-value: P=0.002, (Sig). Cut-point: 70 IU/L Sensitivity: 95% Specificity: 98% PPV: 99% NPV: 90.7% This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 15 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 17 Elmizadeh et al. (24) 2012 Mean age of participants in Ep group: 27.4±6.1 Mean age of participants in intrauterine pregnancy: 26.4±6.5 Mean gestational age in EP group: 7.9±1.8 weeks Mean gestational age in intrauterine pregnancy: 8.5±1.7 Total sample size: 55 Groups of study: 2 groups of patients: EP (26), Normal Intrauterine pregnancy (29). Method of measuring CPK: Kinetic UV-Method Time of sampling: Before any invasive interven- tion Reference test to confirm ectopic pregnancy: Not reported Mean level (±SD) of CPK in tubal Ectopic pregnancies(IU/l): 156±93.6 Mean level (±SD)of CPK in intra uterine pregnancies(IU/l): 58.63±31.5 p-value: pËĆ0.0001, (Sig). Mean level (±SD) of CPK in Intact Ectopic pregnancy(IU/l): 104.3±21.4 Mean level (±SD) of CPK in ruptured Ectopic pregnancy(IU/l): 220.8±100.5 P-value: P=0.002, (Sig). sensitivity: 92% specificity: 86% PPV: 85.7% NPV: 92.5% 18 Asgharnia et al. (2) 2012 Mean age of participants: 16-40 Mean gestational age: First-trimester Total sample size: 111 Groups of study: 3 groups of study; Tubal ectopic pregnancy (n=37) Threatened abortion (n=37) Normal intra-uterine preg- nancy (n=37). Method for measuring CPK: Photometric pars-azmun kit at 37oC Time of sampling: Before any invasive proce- dure Reference test to confirm ectopic pregnancy: Sonography and β-hCG level Mean level (±SD) of CPK in Intact Ectopic pregnancies (IU/l): 96.27±63.9 Mean level (±SD) of CPK in normal pregnancies (IU/l): 48.94±19.2 Mean level (±SD) of CPK in threatened abortions (IU/l): 55.37±14.1 p-value: p<0.0001, (Sig). Mean level (±SD) of CPK-MB in Ectopic pregnancies (IU/l): 15.62±5.2 Mean level (±SD) of CPK-MB in threatened abortions (IU/l) : 17.32±6.9 Mean level (±SD) of CPK-MB in normal pregnancies (IU/l): 15.1±4.7 P-value: P=0.219, (NS). Sensitivity: Not reported Specificity: Not reported 19 Kruchkovich et al. (8) 2012 Mean age of participants: 29.2 years Mean gestational age: 5.6 weeks Total sample size: 79 Groups of study: 2 groups of patients; EP (n=51) Normal pregnancy (n=28). Method for measuring CPK: Kinetic UV test Time of sampling: On admission Reference test to confirm ectopic pregnancy Vaginal ultrasound and serial beta hCG testing. Mean level (±SD) of CPK in Intact Ectopic pregnancies(U/l): 80.90±62.13 Mean level(±SD) of CPK in intra uterine pregnancies (U/l): 74.9±51.6 P-value: P=0.66, (NS). Mean level (±SD) of CPK-MB in Intact Ectopic pregnancies(U/l): 11.1 ± 8.2 Mean level (±SD) of CPK-MB in intra uterine pregnancies (U/l): 74.9±51.6 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 16 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 19 Kruchkovich et al. (8) 2012 Mean age of participants: 29.2 years P-value: 0.39 Sensitivity: Not reported Specificity: Not reported 20 Ghahiri et al. (25) 2012 Mean age of participants of EP group: 28.62 ± 4.97 Mean age of participants of non-EP group: 27.58 ± 4.53 Mean gestational age: First trimester Total sample size: 106 Groups of study: 2 groups of patients; EP (n=53), Non-EP (n=53). Method of measuring CPK: Not reported Time of sampling: On admission Reference test to confirm ectopic pregnancy: Transvaginal sonography, beta-hCG Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): Not reported Mean level (±SD) of CPK in non-Ectopic pregnancies(IU/l): there Not reported p-value of CPK level and the type of pregnancy: P=0.0001, (Sig). p-value of CPK-MB level and the type of pregnancy: P=0.003, (Sig). Mean gestational age: First trimester Total sample size: 106 Groups of study: 2 groups of patients; EP (n=53), Non-EP (n=53). Method of measuring CPK: Not reported Time of sampling: On admission Reference test to confirm ectopic pregnancy: Transvaginal sonography, beta-hCG Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): Not reported Mean level (±SD) of CPK in non-Ectopic pregnancies(IU/l): there Not reported p-value of CPK level and the type of pregnancy: P=0.0001, (Sig). Cut-point: 61 IU/L Sensitivity: 69.81% Specificity: 64.15% PPV: 66.07% NPV: 68% PLR5 : 1.95 NLR6 : 0.49 p-value: 0.0001, (Sig). AUC: 0.692 Cut-point for CPK-MB: 15.6 IU/L Sensitivity: 71.7% Specificity: 56.6% PPV: 62.29% NPV: 66.7% PLR : 1.65 NLR : 0.5 AUC: 0.647 21 Soundravally et al. (4) 2013 Mean age of participants in abortion group: 24.2±4 Mean gestational age in normal pregnancy: 5.4±2.1 weeks Mean gestational age in abortion: 5.2±1.2 weeks Mean gestational age in EP: 4.6±1.5 weeks Total sample size: 63 Groups of study: 2 groups of patients; Rup- tured EP (n=32), Intrauter- ine abortion and normal pregnancies (n=31). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 17 Archives of Academic Emergency Medicine. 2020; 8 (1): e9 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 21 Soundravally et al. (4) 2013 Mean age of participants in abortion group: 24.2±4 Method of measuring CPK: Immuno-inhibition method, in an auto-mated analyzer Time of sampling: At the time of presentation prior to surgical intervention Reference test to confirm ectopic pregnancy: Clinical assessment, beta-hCG and transvaginal ultrasonogra- phy. Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 305±357 Mean level (±SD)of CPK in normal pregnancies(IU/l): 93±35 Mean level (±SD) of CPK in abortions (IU/l): 87±71 p-value: p< 0.05, (Sig). Mean level (±SD) of CPK-MB% in Intact Ectopic pregnancies: 6±8 Mean level (±SD)of CPK-MB% in normal pregnancies: 14±6 Mean level (±SD) of CPK-MB% in abortions: 19±15 p-value: p< 0.05, (Sig). Cut-point for CPK: 147 IU/L Sensitivity: 72% Specificity: 89% Cut-point for CPK-MM and CPK-MB% respectively: 132 IU/L, 10 AUC: 0.882 Sensitivity: 72% Specificity: 93% AUC: 0.851 Sensitivity: 88% Specificity: 68% 22 Abdullateef (26) 2013 Mean age of participants in EP group: 28.97±0.957 Mean age of participants in abortion group: 32.05±1.95 Mean age of participants in normal pregnancy: 25.8±1.139 Mean gestational age: Not reported Total sample size: 81 Groups of study: 3 groups of patients; EP (n=40), Intrauterine abortion (n=17), Normal pregnancy (n=24). Method of measuring CPK: Spectrophotometric analysis Time of sampling: On admission Reference test to confirm ectopic pregnancy: Clinical assessment and transvaginal ultrasonography. Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): Not reported Mean level (±SD) of CPK in intra uterine pregnancies(IU/l): Not reported Mean level (±SD) of CPK in abortions(IU/l): Not reported AUC: 0.903 (95%CI: 0.831–0.975) p-value: p< 0.001, (Sig). cut-point for CPK: 29.43 IU/L sensitivity: 92% specificity: 100% PPV: 100% NPV: 96% Cut-point for CPK-MB: 4.55 IU/L sensitivity: 81.64% specificity: 84.3% PPV: 71.4% NPV: 71.4% This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Ghorbani et al. 18 Table 1: Characteristics of studies included in the review NO 1st author, Year of publication Research information 23 Shafi et al. (7) 2016 Mean age of participants: Not reported Mean gestational age: Not reported Total sample size: 175 Groups of study: 2 groups of patients; EP (n=100), Normal preg- nancy (n=75). Method of measuring CPK: UV kinetic method-NAC Time of sampling: Before any invasive proce- dure. Reference test to confirm ectopic pregnancy: routine investigations and ultrasonography Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 97.64±33.08 Mean level (±SD) of CPK in normal pregnancies(IU/l): 53.20±9.75 Mean level (±SD) of CPK in ruptured tubal pregnancies(IU/l): 111.71±41.56 Mean level (±SD) of CPK in unruptured tubal pregnancies(IU/l): 84.12±11.36 p-value: pËĆ0.001, (Sig). AUC: 86.4% Sensitivity: Not reported Specificity: Not reported 24 Ganta et al. (27) 2017 Mean age of participants: 20-40 Mean gestational age: Not reported Total sample size: 120 Groups of study: 3 groups of patients; EP (n=40), Abortion (40), Nor- mal pregnancy (n=40). Method of measuring CPK: NAC activated with Beck- man Coulter AU480. Time of sampling: Before any invasive proce- dure Reference test to confirm ectopic pregnancy: beta-hCG, sonography, La- paroscopy , Laparotomy Mean level (±SD) of CPK in Intact Ectopic pregnancies(IU/l): 91.55±30.43 Mean level (±SD) of CPK in ruptured Ectopic pregnancies(IU/l): 97.26±25.97 Mean level (±SD) of CPK in unruptured Ectopic pregnancies(IU/l): 63.82±34.9 Mean level (±SD) of CPK in normal pregnancies(IU/l): 36.92±6.44 Mean level (±SD) of CPK in abortions(IU/l): 43.95±11.96 p-value of between 3 groups: p<0.0001, (Sig). p-value of ruptured and unruptured EP: P=0.015, (Sig). sensitivity: Not reported specificity: Not reported 1. Significant 2. Not Significant. 3. Area Under the receiver operating characteristic (ROC) Curve 3. Area Under the receiver operating characteristic (ROC) Curve 4. smooth muscle heavy-chain myosin 5. positive likelihood ratio 6. negative likelihood ratio SD: standard deviation; CK/CPK: creatine phosphokinase; EP: ectopic pregnancy; Sig: significant; PPV: positive predictive value; NS: not significant; AUC: area under the receiver operating characteristic (ROC) curve; NPV: negative predictive value; GA: gestational age; SMHC: smooth muscle heavy-chain myosin; PLR: positive likelihood ratio; NLR: negative likelihood ratio; NAC: N-acetyl-cystein. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods: Results Discussion Conclusion Declarations: References