Vaginal Misoprostol for Overcoming Inadequate Colposcopies: A Meta-analysis of Randomized Controlled Trials Vasilios Pergialiotis, MD, MSc, PhD,1,2 Dimitrios-Efthymios Vlachos, MD, PhD,2 Eleni Pitsouni, MD, MSc,3 Despina Perrea, PhD,1 and Georgios D. Vlachos, MD, PhD2
Objective: Inadequate colposcopic results due to inadequate visualization of the cervical transformation zone is a diagnostic problem that is encountered in approximately 10% to 15% of these procedures. The objective of the present systematic review and meta-analysis was to investigate whether misoprostol effectively converts inadequate colposcopic examinations to adequate. Materials and Methods: We searched MEDLINE (1966Y2014), Scopus (2004Y2014), Popline (1974Y2014), ClinicalTrials.gov (2008Y2014), CENTRAL (1999Y2014), and Google Scholar (2004Y2014) search engines along with reference lists of all electronically retrieved articles. For the meta-analysis of selected indices, we used the RevMan 5.2 program. Results: Treatment with misoprostol significantly increases the rates of adequate colposcopic examinations (odds ratio [OR] = 6.78, 95% confidence interval [CI] = 2.94Y15.61). Its principal adverse effect is abdominal pain (OR = 10.19, 95% CI = 2.19Y47.45). Neither nausea (105 women, random effects model [REM], OR = 4.99, 95% CI = 0.54Y45.71) nor fever (111 women, REM, OR = 3.90, 95% CI = 0.59Y25.56) or diarrhea (111 women, REM, OR = 2.21, 95% CI = 0.49Y10.00) was found increased among women receiving misoprostol. The conversion rates toward an adequate examination ranged between 55.5% and 78.9% in the misoprostol group. Conclusions: According to our meta-analysis, misoprostol seems to improve the conversion rates from inadequate colposcopic examinations to adequate diagnoses. However, firm results to generalize our findings among specific populations, such as those already having a previous conization, are precluded by the small number of enrolled studies. Thus, future research in the field becomes necessary. Key Words: misoprostol, inadequate, unsatisfactory, colposcopy, Pap test (J Lower Gen Tract Dis 2015;19: 257Y261)
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olposcopy is considered to be one of the most important diagnostic tools in cervical cancer prevention. To reach firm conclusions, physicians should be able to identify the external and internal borders of the transformation zone. However, among specific categories of women, such as menopausal women and those having a previous cervical conization, this is not always possible, rendering the results of the examination inadequate.1 The rates of inadequate colposcopies vary in the international literature, ranging between 10% and 15% according to early reports.2,3 The American Society for
1
Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, 1st Department of Obstetrics and Gynecology, and 33rd Department of Obstetrics and Gynecology, Athens University, Medical School, Alexandra Hospital, Athens, Greece Reprint requests to: Pergialiotis Vasilios, MD, 6, Danaidon str. Halandri 15232, Greece. E-mail: [email protected] The authors have declared they have no conflicts of interest. The authors have no funding to disclose. * 2015, American Society for Colposcopy and Cervical Pathology
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Colposcopy and Cervical Pathology (ASCCP) proposes that women with early preinvasive lesions should be followed up conservatively, provided an adequate colposcopic examination has precluded high-grade lesions.4 Unfortunately, current knowledge gives little space for recommendations in the case of women with inadequate colposcopic results. Nevertheless, the ASCCP currently suggests that women with a cytologic result of atypical squamous cells Y cannot exclude high-grade squamous intraepithelial lesion and an inadequate colposcopic result should be offered an excisional diagnostic procedure, whereas those with a low-grade squamous intraepithelial lesion and an inadequate colposcopic result might benefit from endocervical sampling.4 In this context, we find it essential to find new treatment modalities that will increase the rates of women with an adequate examination. This way we can minimize the number of excisional diagnostic operations that are related to adverse pregnancy outcomes.5 Many studies engage with the possible management of inadequate colposcopic results. Despite that, however, there is still no optimal treatment that could facilitate the observation of the transformation zone, thus avoiding the dilemma of performing a cervical biopsy or, alternatively, of observing the progress of patients with no disease or with low-grade lesions at routine cytology.6,7 Previous studies have assessed the effect of estrogen therapy and mechanical cervical dilatation in overcoming an inadequate colposcopic result; however, their methodological quality is far from adequate because their majority lacks randomization.8Y12 During the last decade, a number of randomized trials have investigated whether misoprostol could effectively convert an inadequate colposcopic result to adequate. The purpose of the present systematic review was to accumulate their results to provide implications for current clinical practice and future research.
MATERIALS AND METHODS Study Design The present study was designed according to the PRISMA guidelines.13 Eligibility criteria were predetermined by the authors. No language or date restrictions were applied during the literature search. All prospective randomized controlled trials (RCTs) assessing the impact of misoprostol on inadequate colposcopic examinations were included in the present systematic review. Prospective non-RCTs, retrospective studies, and case reports were excluded from the present systematic review. Meta-analysis was only performed in the case of RCTs that compared patients receiving misoprostol to patients receiving placebo therapy. Two of the authors (V.P. and D.V.) abstracted and tabulated independently all predetermined data to prestructured forms. All discrepancies between these 2 reviewers were resolved by the consensus of all authors.
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Literature Search and Data Collection MEDLINE (1966Y2014), Scopus (2004Y2014), Popline (1974Y2014), ClinicalTrials.gov (2008Y2014), Cochrane Central Register of Controlled Trials (CENTRAL) (1999Y2014), and Google Scholar (2004Y2014) search engines were used in our primary search, along with the reference lists of electronically retrieved articles. We restricted our search by minimizing the number of keywords to assess an eligible number that could be hand searched, without endangering loss of potential articles. All the articles that met or were presumed to meet the inclusion criteria were retrieved in full text. Figure 1 depicts our search strategy. We searched MEDLINE using the MeSH terms (‘‘misoprostol’’[MeSH Terms] OR ‘‘misoprostol’’[All Fields]) AND (‘‘colposcopy’’[MeSH Terms] OR ‘‘colposcopy’’[All Fields]) and the terms (‘‘prostaglandins’’[MeSH Terms] OR ‘‘prostaglandins’’[All Fields]) AND (‘‘colposcopy’’[MeSH Terms] OR ‘‘colposcopy’’[All Fields]). Scopus and CENTRAL were also searched using the terms ‘‘misoprostol colposcopy’’ and ‘‘prostaglandins colposcopy.’’ ClinicalTrials.gov and Popline were searched using the term ‘‘colposcopy.’’ For Google Scholar, we used the terms ‘‘misoprostol, colposcopy, prostaglandins.’’
Quality Assessment We used the modified Jadad score to assess the methodological quality of the included RCTs, according to the following criteria: description of the studies as randomized along with details of randomization, description of the studies as doubleblind, details of double-blinding procedure, information on withdrawals, and allocation concealment.14 One point was added for the presence of each one of them, leading to a maximum score of 5. The level of evidence of each study (see Table 1) was defined according to the definitions of the Oxford Centre for Evidence-Based Medicine.15
Statistical Analysis Statistical meta-analysis was performed using the RevMan 5.2 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Confidence intervals (CIs) were set at 95%. The heterogeneity between included studies was significant because of the discrepancies in the amount of administered misoprostol and in the interval between its administration and second colposcopy; therefore, pooled odds ratios (ORs) and 95% CIs for all primary and secondary outcomes were calculated, by using the DerSimonian-Laird random
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effects model (REM). Publication bias was not assessed because of the heterogeneity of included studies and because of the small number of studies included in the present meta-analysis, factors that may significantly distort this type of analysis.16
Definition of Tabulated Indices In Table 1, we accumulated the principal characteristics that differed between the included studies and certain demographic characteristics of enrolled women (age and menopausal status). In Table 2, we inserted the number of women who had a conversion from an inadequate colposcopic result to an adequate one and the most frequent adverse effects that were encountered after the administration of all regimens (including fever, pain from abdominal cramping, nausea and vomiting, and diarrhea). We predetermined that the conversion rates of inadequate results to adequate would constitute the primary outcome of our meta-analysis. Consequently, the observed adverse effects were predefined as secondary outcomes.
RESULTS Included Studies Five high-quality level of evidence 1 RCTs were finally included in the present systematic review, involving 214 women.17Y21 Four of them were included in the metaanalysis,17Y20 whereas the fifth one was excluded because it compared misoprostol with vaginal estrogen (control group).21
Characteristics of Studies Included in the Meta-analysis In all of the 4 studies included in the meta-analysis, the sole inclusion criterion was the inability to adequately visualize the entire transformation zone.17Y20 Randomization was computer generated. Researchers used pyridoxine as placebo because it was identical to misoprostol tablets and has no active effect on the cervix. The tablets were applied in the posterior fornix. Aggarwal et al.,17 Thanapprapasr et al.,18 and Thavaramara et al.19 excluded from their study women with known hypersensitivity to prostaglandins, pregnant women, and those with cytologic or colposcopic evidence of invasive carcinoma. Tungmunsakulchai et al.20 additionally excluded women with a history of cervical excisional procedure. The dosage of the administered misoprostol and the latency period
FIGURE 1. Search strategy plot.
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5
5
4
5
3
DB-RCT
DB-RCT
DB-RCT
DB-RCT
RCT
Type of study Jadad 19 vs 20
24 vs 22
20 vs 20
18 vs 16
30 vs 27
No. patients
Administered regimen
400 Kg of misoprostol vs 2 tablets of pyridoxine (placebo) 6 h before second colposcopy 400 Kg of misoprostol vs 2 tablets of pyridoxine (placebo) 6 h before second colposcopy 400 Kg of misoprostol vs 2 tablets of pyridoxine (placebo) 12 h before second colposcopy 200 Kg of misoprostol vs (placebo) 4 h before second colposcopy 200 Kg of misoprostol 6 h before second colposcopy vs 50 Kg of estradiol on a 7-d course before colposcopy
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15/19 6/30 10/18 13/19 17/24
vs 6/20 vs 2/27 vs 0/16 vs 5/19 vs 19/22
Adequate colposcopy
Fever 0/19 vs 0/20 N/A 2/18 vs 0/16 3/19 vs 1/19 2/24 vs 0/22
NS 4/30 vs 0/27 5/18 vs 1/16 8/19 vs 0/19 5/24 vs 0/22
Pain
N/A 1/30 vs 0/27 N/A 3/19 vs 0/19 3/24 vs 3/22
Nausea
N/A
N/A
4/20 vs 10/20 3/20 vs 2/20
4/18 vs 1/16
2/19 vs 0/20 N/A 2/18 vs 0/16 2/19 vs 2/19 N/A
Diarrhea
1
1
1
1
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Aggarwal et al. (2006) Thanapprapasr et al. (2010) Thavaramara et al. (2010) Tungmunsakulchai et al. (2010) Makkar et al. (2014)
Author (year)
TABLE 2. Conversion Rates of Inadequate Examinations to Adequate and Adverse Effects Related to Misoprostol Administration
N/A
43.8 vs 49.5
N/A
Nulliparity Level of evidence
20/30 vs 17/27 5/30 vs 8/27
N/A
Menopause
50.0 (33Y74) vs 52.5 (32Y67) 10/18 vs 7/16
49.7 T 9.2 vs 52.0 T 7.6
N/A
Age (y)
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Level of evidence was extracted according to the definitions of the Oxford Centre for Evidence-Based Medicine. DB-RCT indicates double-blind randomized controlled trial; RCT, randomized controlled trial.
Aggarwal et al. (2006) Thanapprapasr et al. (2010) Thavaramara et al. (2010) Tungmunsakulchai et al. (2010) Makkar et al. (2014)
Author (year)
TABLE 1. Characteristics of Included Studies and Demographics of Patients (Misoprostol vs Control Group)
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between its administration and the repetition of the procedure differed among included studies (see Table 1).
Primary Outcome Misoprostol treatment significantly increased the rates of inadequate colposcopic result (168 women, REM, OR = 6.78, 95% CI = 2.94Y15.61; data from 4 studies17Y20; see Figure 2).
Secondary Outcomes Only abdominal pain due to cramping (129 women, REM, OR = 10.19, 95% CI = 2.19Y47.45; data from 3 studies18Y20) was most prevalent among women receiving misoprostol. Neither nausea (105 women, REM, OR = 4.99, 95% CI = 0.54Y45.71; data from 2 studies [18, 20]) nor fever (111 women, REM, OR = 3.90, 95% CI = 0.59Y25.56; data from 3 studies17,19,20) or diarrhea (111 women, REM, OR = 2.21, 95% CI = 0.49Y10.00; data from 3 studies17,19,20) was found increased among women receiving misoprostol.
DISCUSSION Overcoming barriers that may hinder precise colposcopic examination is essential to ensure that women are not endangered by concealed cervical pathologic results. Although current guidelines suggest that women with benign low-grade pathologic results at routine cytology and inadequate colposcopic results can be safely followed up by means of conservative observation or endocervical sampling, it remains undisputed that physicians would prefer an accurate, noninvasive, and timely diagnosis.
Findings and Interpretation of Our Study Our meta-analysis suggests that misoprostol treatment adequately improves the diagnosis when an inadequate colposcopic result is encountered. However, its effect is counterbalanced by certain minor adverse effects. An important observation of our systematic review is that, with the exception of 1 study,18 the conversion rates to an adequate examination ranged between 55.5% and 78.9%. Consequently, one should expect a significant number of those who would at least experience pain from abdominal cramping, which is by far the most prevalent adverse effect of misoprostol (ranging between 13.3% and 42.1% in our study). Referral textbooks suggest that low-dose vaginal estrogen could improve an inadequate colposcopic examination. However, the studies published in the international literature are limited in number and methodological accuracy. In our systematic review, 1 study assessed the efficacy of 200 Kg of misoprostol 6 hours before a second colposcopy compared to a 7-day estrogen course that was followed by a second colposcopy.21 The researchers concluded that both treatments resulted in comparable
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conversion rates of inadequate examination to adequate (17/24 vs 19/22, p = .4). However, they also observed that abdominal cramping was marginally more prevalent in the misoprostoltreated group (5/24 vs 0/22, p = .05).
Strengths and Weaknesses of Our Study Our study’s main strength relies on the high quality of the included randomized trials. The computer-generated randomization that was adopted in all included studies precludes selection bias. Our study’s main disadvantages are the small number of enrolled patients and the significant heterogeneity of the included studies. In this context, publication bias was not investigated because it could lead to false results. Lastly, studies included in the present meta-analysis did not substratify women according to their family planning status. Therefore, we could not investigate the effect of misoprostol among women with inadequate colposcopic results, who were willing to conceive in the future.
Implications for Future Clinical Practice Current guidelines from the ASCCP suggest that women with cervical pathologic results (including atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) and inadequate colposcopic results might benefit from endocervical sampling.4 In this context, it seems that misoprostol could increase the rates of a timely diagnosis, minimizing the number of those cases that ultimately require such a procedure. Furthermore, its mode of action ensures patient compliance because it gives them the opportunity to finish the examination in a single day. Given the fact that its adverse effects are expected to diminish for a period of hours, physicians could consider it as a treatment alternative to decrease the rates of inadequate examinations and endocervical samplings.
Future Research Further studies are needed in the field to generalize our results. Future research should scrutinize specific groups, such as premenopausal women who wish to conceive in the future, postmenopausal women, and women offered a previous cervical conization. It is our belief that it is essential to stratify women because the response rates may differ among the aforementioned groups. Especially in the case of women who desire fertility, future studies should investigate whether misoprostol effectively reduces the number of excisional diagnostic procedures, which are related to adverse obstetric outcomes. Furthermore, it is imperative to identify the minimum required dosage of misoprostol and the interval between its administration and second colposcopy, which effectively increases adequate examinations and together minimizing its adverse effects.
FIGURE 2. Conversion rates to satisfactory colposcopic examinations. The overall effect was statistically significant (p G .001). Vertical line, ‘‘no difference’’ point between the two regimens; squares, mean differences; diamonds, pooled mean differences for all studies; horizontal lines, 95% confidence interval (CI).
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CONCLUSIONS According to our meta-analysis, misoprostol seems to improve the conversion rates from inadequate colposcopic examinations to adequate diagnoses. However, firm results to generalize our findings among specific populations, such as those already having a previous conization, are precluded by the small number of enrolled studies. Thus, future research in the field becomes necessary. REFERENCES 1. Freeman-Wang T, Walker P. Colposcopy in special circumstances: pregnancy, immunocompromise, including HIV and transplants, adolescence and menopause. Best Pract Res Clin Obstet Gynaecol 2011;25:653Y65. 2. Kohan S, Beckman EM, Bigelow B, Carp M, Douglas GW. Colposcopy and the management of cervical intraepithelial neoplasia. Gynecol Oncol 1977;5:27Y39. 3. Stern JL, Major C, Van Le L. Preventing cervical conization by achieving satisfactory colposcopy with hygroscopic cervical dilators. Am J Obstet Gynecol 1990;163:176Y7. 4. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013;17:S1Y27. 5. Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG 2011;118:1031Y41. 6. Massad LS, Tate N, Cejtin E, Collins YC. Quantifying the risk of cervical intraepithelial neoplasia in women with unsatisfactory colposcopy results. J Low Genit Tract Dis 2005;9:23Y8. 7. Day T, Weitzen S, Cooper AS, Boardman LA. Should unsatisfactory colposcopy necessitate treatment of cervical intraepithelial neoplasia 1? J Low Genit Tract Dis 2008;12:11Y5. 8. Johnson N, Brady J. Dilating the cervix medically to overcome an unsatisfactory colposcopy: 5 year follow up. Eur J Obstet Gynecol Reprod Biol 1996;69:125Y7. 9. Prendiville WJ, Davies WA, Davies JO, Shepherd AM. Medical dilatation of the non-pregnant cervix: the effect of ethinyl oestradiol on the visibility of the transformation zone. Br J Obstet Gynaecol 1986;93:508Y11.
* 2015, American Society for Colposcopy and Cervical Pathology
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10. Kishi Y, Inui S, Sakamoto Y, Mori T. Colposcopy for postmenopausal women. Gynecol Oncol 1985;20:62Y70. 11. Borgatta L, Lopatinsky I, Shaw FM. Overcoming unsatisfactory colposcopy. Use of osmotic dilators. J Reprod Med 1997;42:271Y5. 12. McCord ML, Stovall TG, Summitt RLJr, Lipscomb GH, Collins KW, Parsons LH. Synthetic hygroscopic cervical dilator use in patients with unsatisfactory colposcopy. Obstet Gynecol 1995;85:30Y2. 13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1Y34. 14. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1Y12. 15. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924Y6. 16. Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ 2007;176:1091Y6. 17. Aggarwal R, Suneja A, Agarwal N, Mishra K. Role of misoprostol in overcoming an unsatisfactory colposcopy: a randomized double-blind placebo-controlled clinical trial. Gynecol Obstet Invest 2006;62:115Y20. 18. Thanapprapasr D, Wilailak S, Ayudhya NI, Lertkhachonsuk AA, Likittanasombut P, Chittithaworn S, et al. Can vaginal misoprostol effectively increase rate of a satisfactory colposcopy? A randomized double-blind placebo-controlled trial. Jpn J Clin Oncol 2010;40:203Y7. 19. Thavaramara T, Tangjitgamol S, Manusirivithaya S, Pataradool K. A randomized double-blind placebo-controlled trial to evaluate the effect of vaginal misoprostol in the modification of gross cervical anatomy in patients with unsatisfactory colposcopy. Vajira Med J 2010;54:239Y50. 20. Tungmunsakulchai R, Sripipattanakul M. Misoprostol versus placebo for unsatisfactory colposcopic finding: a randomized controlled trial. Thai J Obstet Gynecol 2010;18:134Y8. 21. Makkar B, Batra S, Gandhi G, Zutshi V, Goswami D. Vaginal misoprostol versus vaginal estradiol in overcoming unsatisfactory colposcopy. Gynecol Obstet Invest 2014;77:176Y9.
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Objective: Inadequate colposcopic results due to inadequate visualization of the cervical transformation zone is a diagnostic problem that is encountered in approximately 10% to 15% of these procedures. The objective of the present systematic review and meta-analysis was to investigate whether misoprostol effectively converts inadequate colposcopic examinations to adequate. Materials and Methods: We searched MEDLINE (1966Y2014), Scopus (2004Y2014), Popline (1974Y2014), ClinicalTrials.gov (2008Y2014), CENTRAL (1999Y2014), and Google Scholar (2004Y2014) search engines along with reference lists of all electronically retrieved articles. For the meta-analysis of selected indices, we used the RevMan 5.2 program. Results: Treatment with misoprostol significantly increases the rates of adequate colposcopic examinations (odds ratio [OR] = 6.78, 95% confidence interval [CI] = 2.94Y15.61). Its principal adverse effect is abdominal pain (OR = 10.19, 95% CI = 2.19Y47.45). Neither nausea (105 women, random effects model [REM], OR = 4.99, 95% CI = 0.54Y45.71) nor fever (111 women, REM, OR = 3.90, 95% CI = 0.59Y25.56) or diarrhea (111 women, REM, OR = 2.21, 95% CI = 0.49Y10.00) was found increased among women receiving misoprostol. The conversion rates toward an adequate examination ranged between 55.5% and 78.9% in the misoprostol group. Conclusions: According to our meta-analysis, misoprostol seems to improve the conversion rates from inadequate colposcopic examinations to adequate diagnoses. However, firm results to generalize our findings among specific populations, such as those already having a previous conization, are precluded by the small number of enrolled studies. Thus, future research in the field becomes necessary. Key Words: misoprostol, inadequate, unsatisfactory, colposcopy, Pap test (J Lower Gen Tract Dis 2015;19: 257Y261)
C
olposcopy is considered to be one of the most important diagnostic tools in cervical cancer prevention. To reach firm conclusions, physicians should be able to identify the external and internal borders of the transformation zone. However, among specific categories of women, such as menopausal women and those having a previous cervical conization, this is not always possible, rendering the results of the examination inadequate.1 The rates of inadequate colposcopies vary in the international literature, ranging between 10% and 15% according to early reports.2,3 The American Society for
1
Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, 1st Department of Obstetrics and Gynecology, and 33rd Department of Obstetrics and Gynecology, Athens University, Medical School, Alexandra Hospital, Athens, Greece Reprint requests to: Pergialiotis Vasilios, MD, 6, Danaidon str. Halandri 15232, Greece. E-mail: [email protected] The authors have declared they have no conflicts of interest. The authors have no funding to disclose. * 2015, American Society for Colposcopy and Cervical Pathology
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Colposcopy and Cervical Pathology (ASCCP) proposes that women with early preinvasive lesions should be followed up conservatively, provided an adequate colposcopic examination has precluded high-grade lesions.4 Unfortunately, current knowledge gives little space for recommendations in the case of women with inadequate colposcopic results. Nevertheless, the ASCCP currently suggests that women with a cytologic result of atypical squamous cells Y cannot exclude high-grade squamous intraepithelial lesion and an inadequate colposcopic result should be offered an excisional diagnostic procedure, whereas those with a low-grade squamous intraepithelial lesion and an inadequate colposcopic result might benefit from endocervical sampling.4 In this context, we find it essential to find new treatment modalities that will increase the rates of women with an adequate examination. This way we can minimize the number of excisional diagnostic operations that are related to adverse pregnancy outcomes.5 Many studies engage with the possible management of inadequate colposcopic results. Despite that, however, there is still no optimal treatment that could facilitate the observation of the transformation zone, thus avoiding the dilemma of performing a cervical biopsy or, alternatively, of observing the progress of patients with no disease or with low-grade lesions at routine cytology.6,7 Previous studies have assessed the effect of estrogen therapy and mechanical cervical dilatation in overcoming an inadequate colposcopic result; however, their methodological quality is far from adequate because their majority lacks randomization.8Y12 During the last decade, a number of randomized trials have investigated whether misoprostol could effectively convert an inadequate colposcopic result to adequate. The purpose of the present systematic review was to accumulate their results to provide implications for current clinical practice and future research.
MATERIALS AND METHODS Study Design The present study was designed according to the PRISMA guidelines.13 Eligibility criteria were predetermined by the authors. No language or date restrictions were applied during the literature search. All prospective randomized controlled trials (RCTs) assessing the impact of misoprostol on inadequate colposcopic examinations were included in the present systematic review. Prospective non-RCTs, retrospective studies, and case reports were excluded from the present systematic review. Meta-analysis was only performed in the case of RCTs that compared patients receiving misoprostol to patients receiving placebo therapy. Two of the authors (V.P. and D.V.) abstracted and tabulated independently all predetermined data to prestructured forms. All discrepancies between these 2 reviewers were resolved by the consensus of all authors.
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Copyright © 2015 American Society for Colposcopy and Cervical Pathology. Unauthorized reproduction of this article is prohibited.
Pergialiotis et al.
Literature Search and Data Collection MEDLINE (1966Y2014), Scopus (2004Y2014), Popline (1974Y2014), ClinicalTrials.gov (2008Y2014), Cochrane Central Register of Controlled Trials (CENTRAL) (1999Y2014), and Google Scholar (2004Y2014) search engines were used in our primary search, along with the reference lists of electronically retrieved articles. We restricted our search by minimizing the number of keywords to assess an eligible number that could be hand searched, without endangering loss of potential articles. All the articles that met or were presumed to meet the inclusion criteria were retrieved in full text. Figure 1 depicts our search strategy. We searched MEDLINE using the MeSH terms (‘‘misoprostol’’[MeSH Terms] OR ‘‘misoprostol’’[All Fields]) AND (‘‘colposcopy’’[MeSH Terms] OR ‘‘colposcopy’’[All Fields]) and the terms (‘‘prostaglandins’’[MeSH Terms] OR ‘‘prostaglandins’’[All Fields]) AND (‘‘colposcopy’’[MeSH Terms] OR ‘‘colposcopy’’[All Fields]). Scopus and CENTRAL were also searched using the terms ‘‘misoprostol colposcopy’’ and ‘‘prostaglandins colposcopy.’’ ClinicalTrials.gov and Popline were searched using the term ‘‘colposcopy.’’ For Google Scholar, we used the terms ‘‘misoprostol, colposcopy, prostaglandins.’’
Quality Assessment We used the modified Jadad score to assess the methodological quality of the included RCTs, according to the following criteria: description of the studies as randomized along with details of randomization, description of the studies as doubleblind, details of double-blinding procedure, information on withdrawals, and allocation concealment.14 One point was added for the presence of each one of them, leading to a maximum score of 5. The level of evidence of each study (see Table 1) was defined according to the definitions of the Oxford Centre for Evidence-Based Medicine.15
Statistical Analysis Statistical meta-analysis was performed using the RevMan 5.2 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012). Confidence intervals (CIs) were set at 95%. The heterogeneity between included studies was significant because of the discrepancies in the amount of administered misoprostol and in the interval between its administration and second colposcopy; therefore, pooled odds ratios (ORs) and 95% CIs for all primary and secondary outcomes were calculated, by using the DerSimonian-Laird random
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effects model (REM). Publication bias was not assessed because of the heterogeneity of included studies and because of the small number of studies included in the present meta-analysis, factors that may significantly distort this type of analysis.16
Definition of Tabulated Indices In Table 1, we accumulated the principal characteristics that differed between the included studies and certain demographic characteristics of enrolled women (age and menopausal status). In Table 2, we inserted the number of women who had a conversion from an inadequate colposcopic result to an adequate one and the most frequent adverse effects that were encountered after the administration of all regimens (including fever, pain from abdominal cramping, nausea and vomiting, and diarrhea). We predetermined that the conversion rates of inadequate results to adequate would constitute the primary outcome of our meta-analysis. Consequently, the observed adverse effects were predefined as secondary outcomes.
RESULTS Included Studies Five high-quality level of evidence 1 RCTs were finally included in the present systematic review, involving 214 women.17Y21 Four of them were included in the metaanalysis,17Y20 whereas the fifth one was excluded because it compared misoprostol with vaginal estrogen (control group).21
Characteristics of Studies Included in the Meta-analysis In all of the 4 studies included in the meta-analysis, the sole inclusion criterion was the inability to adequately visualize the entire transformation zone.17Y20 Randomization was computer generated. Researchers used pyridoxine as placebo because it was identical to misoprostol tablets and has no active effect on the cervix. The tablets were applied in the posterior fornix. Aggarwal et al.,17 Thanapprapasr et al.,18 and Thavaramara et al.19 excluded from their study women with known hypersensitivity to prostaglandins, pregnant women, and those with cytologic or colposcopic evidence of invasive carcinoma. Tungmunsakulchai et al.20 additionally excluded women with a history of cervical excisional procedure. The dosage of the administered misoprostol and the latency period
FIGURE 1. Search strategy plot.
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5
5
4
5
3
DB-RCT
DB-RCT
DB-RCT
DB-RCT
RCT
Type of study Jadad 19 vs 20
24 vs 22
20 vs 20
18 vs 16
30 vs 27
No. patients
Administered regimen
400 Kg of misoprostol vs 2 tablets of pyridoxine (placebo) 6 h before second colposcopy 400 Kg of misoprostol vs 2 tablets of pyridoxine (placebo) 6 h before second colposcopy 400 Kg of misoprostol vs 2 tablets of pyridoxine (placebo) 12 h before second colposcopy 200 Kg of misoprostol vs (placebo) 4 h before second colposcopy 200 Kg of misoprostol 6 h before second colposcopy vs 50 Kg of estradiol on a 7-d course before colposcopy
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15/19 6/30 10/18 13/19 17/24
vs 6/20 vs 2/27 vs 0/16 vs 5/19 vs 19/22
Adequate colposcopy
Fever 0/19 vs 0/20 N/A 2/18 vs 0/16 3/19 vs 1/19 2/24 vs 0/22
NS 4/30 vs 0/27 5/18 vs 1/16 8/19 vs 0/19 5/24 vs 0/22
Pain
N/A 1/30 vs 0/27 N/A 3/19 vs 0/19 3/24 vs 3/22
Nausea
N/A
N/A
4/20 vs 10/20 3/20 vs 2/20
4/18 vs 1/16
2/19 vs 0/20 N/A 2/18 vs 0/16 2/19 vs 2/19 N/A
Diarrhea
1
1
1
1
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Aggarwal et al. (2006) Thanapprapasr et al. (2010) Thavaramara et al. (2010) Tungmunsakulchai et al. (2010) Makkar et al. (2014)
Author (year)
TABLE 2. Conversion Rates of Inadequate Examinations to Adequate and Adverse Effects Related to Misoprostol Administration
N/A
43.8 vs 49.5
N/A
Nulliparity Level of evidence
20/30 vs 17/27 5/30 vs 8/27
N/A
Menopause
50.0 (33Y74) vs 52.5 (32Y67) 10/18 vs 7/16
49.7 T 9.2 vs 52.0 T 7.6
N/A
Age (y)
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Level of evidence was extracted according to the definitions of the Oxford Centre for Evidence-Based Medicine. DB-RCT indicates double-blind randomized controlled trial; RCT, randomized controlled trial.
Aggarwal et al. (2006) Thanapprapasr et al. (2010) Thavaramara et al. (2010) Tungmunsakulchai et al. (2010) Makkar et al. (2014)
Author (year)
TABLE 1. Characteristics of Included Studies and Demographics of Patients (Misoprostol vs Control Group)
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Pergialiotis et al.
between its administration and the repetition of the procedure differed among included studies (see Table 1).
Primary Outcome Misoprostol treatment significantly increased the rates of inadequate colposcopic result (168 women, REM, OR = 6.78, 95% CI = 2.94Y15.61; data from 4 studies17Y20; see Figure 2).
Secondary Outcomes Only abdominal pain due to cramping (129 women, REM, OR = 10.19, 95% CI = 2.19Y47.45; data from 3 studies18Y20) was most prevalent among women receiving misoprostol. Neither nausea (105 women, REM, OR = 4.99, 95% CI = 0.54Y45.71; data from 2 studies [18, 20]) nor fever (111 women, REM, OR = 3.90, 95% CI = 0.59Y25.56; data from 3 studies17,19,20) or diarrhea (111 women, REM, OR = 2.21, 95% CI = 0.49Y10.00; data from 3 studies17,19,20) was found increased among women receiving misoprostol.
DISCUSSION Overcoming barriers that may hinder precise colposcopic examination is essential to ensure that women are not endangered by concealed cervical pathologic results. Although current guidelines suggest that women with benign low-grade pathologic results at routine cytology and inadequate colposcopic results can be safely followed up by means of conservative observation or endocervical sampling, it remains undisputed that physicians would prefer an accurate, noninvasive, and timely diagnosis.
Findings and Interpretation of Our Study Our meta-analysis suggests that misoprostol treatment adequately improves the diagnosis when an inadequate colposcopic result is encountered. However, its effect is counterbalanced by certain minor adverse effects. An important observation of our systematic review is that, with the exception of 1 study,18 the conversion rates to an adequate examination ranged between 55.5% and 78.9%. Consequently, one should expect a significant number of those who would at least experience pain from abdominal cramping, which is by far the most prevalent adverse effect of misoprostol (ranging between 13.3% and 42.1% in our study). Referral textbooks suggest that low-dose vaginal estrogen could improve an inadequate colposcopic examination. However, the studies published in the international literature are limited in number and methodological accuracy. In our systematic review, 1 study assessed the efficacy of 200 Kg of misoprostol 6 hours before a second colposcopy compared to a 7-day estrogen course that was followed by a second colposcopy.21 The researchers concluded that both treatments resulted in comparable
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conversion rates of inadequate examination to adequate (17/24 vs 19/22, p = .4). However, they also observed that abdominal cramping was marginally more prevalent in the misoprostoltreated group (5/24 vs 0/22, p = .05).
Strengths and Weaknesses of Our Study Our study’s main strength relies on the high quality of the included randomized trials. The computer-generated randomization that was adopted in all included studies precludes selection bias. Our study’s main disadvantages are the small number of enrolled patients and the significant heterogeneity of the included studies. In this context, publication bias was not investigated because it could lead to false results. Lastly, studies included in the present meta-analysis did not substratify women according to their family planning status. Therefore, we could not investigate the effect of misoprostol among women with inadequate colposcopic results, who were willing to conceive in the future.
Implications for Future Clinical Practice Current guidelines from the ASCCP suggest that women with cervical pathologic results (including atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) and inadequate colposcopic results might benefit from endocervical sampling.4 In this context, it seems that misoprostol could increase the rates of a timely diagnosis, minimizing the number of those cases that ultimately require such a procedure. Furthermore, its mode of action ensures patient compliance because it gives them the opportunity to finish the examination in a single day. Given the fact that its adverse effects are expected to diminish for a period of hours, physicians could consider it as a treatment alternative to decrease the rates of inadequate examinations and endocervical samplings.
Future Research Further studies are needed in the field to generalize our results. Future research should scrutinize specific groups, such as premenopausal women who wish to conceive in the future, postmenopausal women, and women offered a previous cervical conization. It is our belief that it is essential to stratify women because the response rates may differ among the aforementioned groups. Especially in the case of women who desire fertility, future studies should investigate whether misoprostol effectively reduces the number of excisional diagnostic procedures, which are related to adverse obstetric outcomes. Furthermore, it is imperative to identify the minimum required dosage of misoprostol and the interval between its administration and second colposcopy, which effectively increases adequate examinations and together minimizing its adverse effects.
FIGURE 2. Conversion rates to satisfactory colposcopic examinations. The overall effect was statistically significant (p G .001). Vertical line, ‘‘no difference’’ point between the two regimens; squares, mean differences; diamonds, pooled mean differences for all studies; horizontal lines, 95% confidence interval (CI).
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CONCLUSIONS According to our meta-analysis, misoprostol seems to improve the conversion rates from inadequate colposcopic examinations to adequate diagnoses. However, firm results to generalize our findings among specific populations, such as those already having a previous conization, are precluded by the small number of enrolled studies. Thus, future research in the field becomes necessary. REFERENCES 1. Freeman-Wang T, Walker P. Colposcopy in special circumstances: pregnancy, immunocompromise, including HIV and transplants, adolescence and menopause. Best Pract Res Clin Obstet Gynaecol 2011;25:653Y65. 2. Kohan S, Beckman EM, Bigelow B, Carp M, Douglas GW. Colposcopy and the management of cervical intraepithelial neoplasia. Gynecol Oncol 1977;5:27Y39. 3. Stern JL, Major C, Van Le L. Preventing cervical conization by achieving satisfactory colposcopy with hygroscopic cervical dilators. Am J Obstet Gynecol 1990;163:176Y7. 4. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013;17:S1Y27. 5. Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG 2011;118:1031Y41. 6. Massad LS, Tate N, Cejtin E, Collins YC. Quantifying the risk of cervical intraepithelial neoplasia in women with unsatisfactory colposcopy results. J Low Genit Tract Dis 2005;9:23Y8. 7. Day T, Weitzen S, Cooper AS, Boardman LA. Should unsatisfactory colposcopy necessitate treatment of cervical intraepithelial neoplasia 1? J Low Genit Tract Dis 2008;12:11Y5. 8. Johnson N, Brady J. Dilating the cervix medically to overcome an unsatisfactory colposcopy: 5 year follow up. Eur J Obstet Gynecol Reprod Biol 1996;69:125Y7. 9. Prendiville WJ, Davies WA, Davies JO, Shepherd AM. Medical dilatation of the non-pregnant cervix: the effect of ethinyl oestradiol on the visibility of the transformation zone. Br J Obstet Gynaecol 1986;93:508Y11.
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10. Kishi Y, Inui S, Sakamoto Y, Mori T. Colposcopy for postmenopausal women. Gynecol Oncol 1985;20:62Y70. 11. Borgatta L, Lopatinsky I, Shaw FM. Overcoming unsatisfactory colposcopy. Use of osmotic dilators. J Reprod Med 1997;42:271Y5. 12. McCord ML, Stovall TG, Summitt RLJr, Lipscomb GH, Collins KW, Parsons LH. Synthetic hygroscopic cervical dilator use in patients with unsatisfactory colposcopy. Obstet Gynecol 1995;85:30Y2. 13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1Y34. 14. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1Y12. 15. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924Y6. 16. Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ 2007;176:1091Y6. 17. Aggarwal R, Suneja A, Agarwal N, Mishra K. Role of misoprostol in overcoming an unsatisfactory colposcopy: a randomized double-blind placebo-controlled clinical trial. Gynecol Obstet Invest 2006;62:115Y20. 18. Thanapprapasr D, Wilailak S, Ayudhya NI, Lertkhachonsuk AA, Likittanasombut P, Chittithaworn S, et al. Can vaginal misoprostol effectively increase rate of a satisfactory colposcopy? A randomized double-blind placebo-controlled trial. Jpn J Clin Oncol 2010;40:203Y7. 19. Thavaramara T, Tangjitgamol S, Manusirivithaya S, Pataradool K. A randomized double-blind placebo-controlled trial to evaluate the effect of vaginal misoprostol in the modification of gross cervical anatomy in patients with unsatisfactory colposcopy. Vajira Med J 2010;54:239Y50. 20. Tungmunsakulchai R, Sripipattanakul M. Misoprostol versus placebo for unsatisfactory colposcopic finding: a randomized controlled trial. Thai J Obstet Gynecol 2010;18:134Y8. 21. Makkar B, Batra S, Gandhi G, Zutshi V, Goswami D. Vaginal misoprostol versus vaginal estradiol in overcoming unsatisfactory colposcopy. Gynecol Obstet Invest 2014;77:176Y9.
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