Contraception 91 (2015) 406 – 411
Original research article
Laminaria vs. vaginal misoprostol for cervical preparation before second-trimester surgical abortion: a randomized clinical trial☆,☆☆ Ron Sagiv⁎, Yossi Mizrachi⁎, Hagit Glickman, Ram Kerner, Ran Keidar, Jacob Bar, Abraham Golan Department of Obstetrics and Gynecology, E. Wolfson Medical Center, Holon, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received 7 October 2014; revised 27 January 2015; accepted 27 January 2015
Abstract Objective: To compare the efficacy and tolerability of vaginal misoprostol and laminaria for cervical preparation before second-trimester surgical abortion. Study design: We performed a prospective, randomized trial comparing midnight administration of misoprostol 600 mcg vaginally to midnight placement of laminaria, before surgical abortions among women at 13–20 weeks of gestation. The primary outcome was preoperative cervical dilation. Secondary outcomes were the need for further dilation, procedure duration and difficulty, immediate complications and side effects. Results: Eighty-four women were randomized, with a median gestational age of 16.5 weeks. The mean time interval between misoprostol and laminaria placement and dilatation and evacuation initiation was 11.0±2.9 and 11.2±2.0 h, respectively (p=.17). Cervical dilation was not greater in the laminaria group as compared to the misoprostol group (12.8 vs. 12.4 mm, respectively; p=.32). No difference was demonstrated regarding the need for additional dilation or the difficulty of the procedure. Procedures performed after laminaria insertion were 1 min longer (median 11 vs. 10 min, p=.04). Participants found laminaria placement more uncomfortable than vaginal misoprostol placement. Other than pain, additional side effects occurred only in the misoprostol group, primarily nausea and vomiting. One participant in the misoprostol group experienced fetal expulsion during the night before the intended procedure. Conclusion: Either vaginal misoprostol or laminaria provides adequate dilation for second-trimester surgical abortion. Laminaria causes more pain at insertion and misoprostol causes more side effects. Implications statement: We found that cervical preparation in an inpatient setting for approximately 11 h with misoprostol 600 mcg vaginally is comparable to 11 h of laminaria. However, given the potential for spontaneous expulsion and more side effects with misoprostol, laminaria is likely a better general option in such a setting. © 2015 Elsevier Inc. All rights reserved. Keywords: Cervical preparation; Misoprostol; Laminaria; Surgical abortion
1. Introduction Dilatation and evacuation (D&E) is the most common mode of second-trimester elective abortion in the United States [1]. Cervical preparation before D&E is essential to
☆
Financial disclosure: No potential conflicts of interest for any of the authors. ☆☆ Clinical trial registration: http://clinicaltrials.gov/show/NCT01678703. ⁎ Corresponding authors. Department of Gynecology & Obstetrics, E. Wolfson Medical Center, 62 Halochamim Street, Holon 58100, Israel. Tel.: + 972 3 502 8329; fax: + 972 3 502 8503. E-mail address: [email protected] (R. Sagiv). http://dx.doi.org/10.1016/j.contraception.2015.01.018 0010-7824/© 2015 Elsevier Inc. All rights reserved.
minimize complications such as cervical trauma, uterine perforation and excessive bleeding [2–6]. The cervix may be prepared with pharmacological agents such as misoprostol, or with mechanical agents such as laminaria. Vaginal, oral or buccal administration of misoprostol has proven successful for cervical preparation in first- and second-trimester surgical abortion. Overall, vaginal administration results in more consistent absorption and better cervical dilation than oral administration [7–12]. Several studies compared the efficacy of misoprostol and osmotic dilators for cervical preparation prior to secondtrimester D&E. A previous randomized trial [13] compared the administration of same-day 400 mcg vaginal misoprostol to overnight laminaria before early second-trimester surgical
R. Sagiv et al. / Contraception 91 (2015) 406–411
abortion. Participants who underwent preparation with laminaria were found to have greater dilatation at the time of the procedure. Moreover, procedures took longer and were technically more challenging after cervical preparation with same-day misoprostol. A second randomized trial [14] compared the efficacy of same-day 400 mcg buccal misoprostol to laminaria inserted the day before D&E among women at 13–19 weeks of gestation. Both regimens were found to have similar low rates of adverse effects. Misoprostol participants were more likely to require additional mechanical dilation. A Chocrane Database Systemic Review [15] assessed all available randomized trials of cervical preparation prior to second trimester D&E. Cervical preparation with osmotic dilators and/or misoprostol was found to be safe and effective. Osmotic dilators appeared to provide superior cervical dilation; however, this difference in cervical dilation did not appear to result in differences in procedure time or complication rates. The Society of Family Planning (SFP) [16] states that the use of misoprostol as an alternative to osmotic tents increases the risk of inadequate cervical dilation. It recommends that only experienced providers capable of managing difficult cervical dilation should use protocols omitting osmotic tent placement prior to D&E. However, the SFP examined only studies that used a short same-day regimen of misoprostol. Our objective was to compare extended administration of 600 mcg vaginal misoprostol with placement of laminaria for cervical preparation before second-trimester surgical abortion.
2. Materials and methods We performed a prospective, unblinded, randomized (1:1) study in 84 patients who underwent D&E for termination of pregnancy at 13–20 weeks of gestation. The study was performed from January 2008 to January 2011 at the Edith Wolfson Hospital in Holon, Israel. The study protocol was approved by the institutional review board. Patients were referred to have surgical termination of pregnancy, and these were performed according to Israeli law after approval from a pregnancy termination committee. Eligible participants were all at least 15 years old and in good general health. Gestational age was confirmed by first-trimester ultrasound examination. Exclusion criteria were allergy to misoprostol, fetal demise, bleeding disorder, current anticoagulation therapy, previous loop electrosurgical excision procedure or conization procedure, multiple gestation and breast-feeding. Patients with previous cesarean scar were not excluded. All participants were hospitalized the day before the procedure. Subjects were randomly assigned to cervical preparation with either misoprostol or laminaria. Randomization was performed using a computer-generated list of random numbers by a researcher not involved in subject recruitment or care. Treatment allocation was concealed by placing assignments in sequentially numbered opaque
407
envelopes. After providing a written informed consent, a research assistant opened the envelope and notified the physician performing the subject's preoperative evaluation of treatment assignment. Participants randomized for laminaria had them placed at midnight before the procedure. The vagina was cleansed with aqueous Betadine® solution. The direction of the cervix was noted, and one to six laminaria tents were placed within the cervical canal using a tenaculum applied to the cervix. The number of laminaria tents was determined by the clinician. Paracervical anesthesia was not performed. Participants assigned for misoprostol had three 200-mcg tablets (a 600-mcg dose) administered vaginally to the posterior fornix at midnight. Subjects who had vaginal bleeding or expulsion of the fetus during the night before the intended procedure were evaluated and, when indicated, transferred immediately to the operating room to complete the evacuation. For the procedure, all subjects received general endotracheal anesthesia. Procedures were performed by four physicians, all of whom had more than 10 years of experience performing D&Es. The operating physicians were not blinded to the treatment arm. The operating physician placed a speculum and then assessed initial cervical dilation by gradual insertion of Hegar dilators, noting the largest dilator that fit through the cervix without resistance. Timing of the procedure was started with the onset of either additional rigid dilation, when required, or introduction of a forceps or suction cannula. Ring forceps were used for the procedures. Procedure time was ended when the last instrument was removed from the uterus. Procedures were performed under ultrasound guidance. Subjects were discharged when medically stable 6–8 h after the procedure. Upon completion of the procedure, the operating physician was asked to rate the difficulty of the procedure on a 5-point Likert scale, defined as: 0=no difficulty, 1=mild difficulty, 2=mild to moderate difficulty, 3=moderate difficulty, 4=moderate to marked difficulty and 5=marked difficulty. Adverse effects were assessed with a series of questionnaires. Pain was assessed using the VAS score (ranging from 1=no pain to 10=the worst possible pain), ranked by the participants at various time periods: immediately after laminaria or misoprostol placement, 3 to 4 h after laminaria or misoprostol placement, and upon discharge from the department. Pain control management was similar in both groups. Upon request, participants were given 1 g dipyrone (Optalgin®) orally. Participants requesting additional analgesia received 75 mg diclofenac (Voltaren®) intramuscularly. If needed, additional dose of dipyrone was given after 6 h, and additional dose of diclofenac was given after 8 h. Other adverse effects were reported by the participants 3 to 4 h after laminaria or misoprostol placement using a yes or no questionnaires. Subjects' demographics, reproductive history and complications were abstracted from the medical record.
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The primary outcome was preoperative cervical dilatation. Secondary outcomes were the need for further dilation, procedure duration and difficulty, side effects and immediate complications. Post hoc sample size calculations showed that with 30 women in each group, the study had 80% power to distinguish a true, between-group difference of 2 mm (SD 2.7 mm) in preoperative vaginal dilation, with a 2-sided alpha of .05. We assumed that a difference less than 2 mm lacks clinical significance. Data were analyzed on SPSS v21.0 statistical analysis software (IBM Inc., USA). Distributions of continuous variables were assessed for normality using the Kolmogorov– Smirnov test (cutoff at pb.1). Normally distributed continuous outcomes were compared by using the two-tailed t test. Continuous variables that were not normally distributed were compared by using the Mann-Whitney U test. Nominal
variables were compared by group using the chi-square test and Fisher's Exact Test as needed. All tests were two sided and considered significant at pb.05. 3. Results A total of 117 women seeking surgical abortion services between 13 and 20 weeks of gestation were assessed for eligibility during the study period, and 84 women were enrolled (Fig. 1). Forty-one subjects were assigned to the misoprostol group, and 43 subjects were assigned to the laminaria group. All participants completed the study and were evaluated. There were no differences in demographic or clinical characteristics between groups (Table 1). The mean number of laminaria inserted in the laminaria group was 3.5±1.9. The mean time interval between laminaria or misoprostol
CONSORT 2010 Flow Diagram
Enrollment
Assessed for eligibility (n=117)
Excluded (n=33) Not meeting inclusion criteria (n=27) Declined to participate (n=6) Other reasons (n=0)
Randomized (n=84)
Allocation Allocated to misoprostol (n=41) Received allocated intervention (n=41)
Allocated to laminaria (n=43) Received allocated intervention (n=43)
Did not receive allocated intervention (n=0)
Did not receive allocated intervention (n=0)
Follow-Up Lost to follow-up (n=0)
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Discontinued intervention (n=0)
Analysis Analysed (n=41) Excluded from analysis (n=0)
Analysed (n=43) Excluded from analysis (n=0)
Fig. 1. CONSORT flowchart.
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placement and D&E initiation was 11.2±2.0 and 11.0±2.9 h, respectively (p=.17). Preoperative cervical dilation did not differ between laminaria and misoprostol groups (12.8 vs. 12.4 mm, respectively; p=.32) (Table 2). Procedures performed after laminaria insertion were 1 min longer than those performed after misoprostol insertion (median of 11 min vs. 10 min, respectively; p=.04). The proportion of cases that required additional dilation and the median level of difficulty of the procedure did not differ between the two groups (Table 2). The majority of the procedures in both groups were rated as either not difficult or mildly difficult. All procedures were completed on a single attempt in both groups. Data regarding pain with cervical preparation administration, during the time between administration and procedure and upon discharge are presented in Table 3. Other than pain, side effects occurred with a frequency of between 2% and 15% only in the misoprostol group, with nausea and vomiting being significantly more frequent (Table 3). In the misoprostol group, one participant experienced uterine bleeding and expulsion of the fetus during the night before the intended procedure. She was transferred immediately to the operating room to complete the evacuation. Gestational age was 13 weeks and 4 days. In five other participants, the fetus was found to be bulging into the vagina upon initiation of the procedure. Fetuses were fully extracted using the ring forceps or by fundal pressure, and the procedures were completed by curettage. Three cases of excessive bleeding during or immediately after the procedure were noted. One case occurred in the laminaria group, necessitated transfusion of 2 units of packed red blood cells. The other two cases of bleeding were in the misoprostol group. The etiology of bleeding was assumed uterine atony in all cases. Subjects were treated with oxytocin and the bleeding ceased with no need for further intervention. 4. Discussion In this small prospective randomized trial, we found that both misoprostol and laminaria placed at midnight are similarly effective for cervical preparation before secondtrimester D&E. No difference was found regarding preoperative cervical dilatation, the need for further dilatation or the difficulty of the procedure. Table 1 Baseline characteristics of the misoprostol and laminaria groups
Age (years) Gestational age (weeks) Nulliparous Previous vaginal deliveries Previous cesarean deliveries
Misoprostol group (n=41)
Laminaria group (n= 43)
p
30 (15–47) 17 (14–20) 21 (51.2%) 15 (36.5%) 6 (14.6%)
29 (17–45) 16 (14–20) 23 (53.4%) 18 (41.8%) 4 (9.3%)
.89 .86 .88 .7 .47
Data are presented as median (range) or n (%).
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Table 2 Clinical outcomes among subjects randomized to laminaria vs. misoprostol for cervical preparation before second-trimester abortion
Interval between misoprostol/laminaria placement and initiation of the procedure (h) Mean initial dilation (mm) Median procedure duration (min) Additional dilation required Median difficulty of procedure (0–5 scale)
Misoprostol (n=41)
Laminaria (n= 43)
p
11.0±2.9
11.2±2.0
.17
12.4±2.7 10 (3–20) 12 (30%) 1 (0–4)
12.8±1.8 11 (5–30) 14 (32%) 1 (0–4)
.32 .03 .8 .4
Data are presented as mean (±standard deviation) or median (range).
Procedures performed after laminaria insertion were 1 min longer. This can be explained by the fact that in the misoprostol group, there were five cases in which the fetus was found to be bulging into the vagina upon initiation of the procedure and was fully extracted using the ring forceps or by fundal pressure. These procedures were later completed only by curettage and therefore were shorter. However, we believe that this small difference in procedure duration lacks clinical importance. Participants found laminaria placement more uncomfortable than misoprostol placement. We assume that the pain related to laminaria insertion is due to grasping of the cervix with the tenaculum and introduction of laminaria tents into the cervical canal. These painful steps are not required while placing misoprostol tablets in the vagina. We did not use cervical anesthesia, which may decrease pain with laminaria insertion. Moreover, paracervical anesthesia might enable the insertion of more laminaria and achievement of wider dilatation. Although the initial cervical dilation and procedure duration and difficulty are important measures of efficacy to consider when selecting a cervical preparation method,
Table 3 Subjects' assessments of adverse effects of misoprostol and laminaria before second-trimester abortion Misoprostol Laminaria p (n= 41) (n=43) Pain a With laminaria or misoprostol placement 1 (1–6) During the night before surgical abortion 5.5 (1–10) After the procedure 1 (1–5) Nausea 6 (15%) Vomiting 5 (12%) Diarrhea 1 (2%) Chills 2 (5%) Fever 2 (5%)
4 (1–10) 3 (1–10) 2 (1–10) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
b.001 .08 .2 .01 .02 .4 .2 .2
Data are presented as median (range) for pain and n (%) for other outcomes. a Visual analog scale, scored from 1 to 10.
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differences in complication rates are also of a great importance. In our study, there were three cases of bleeding during or immediately after the procedure: one case in the laminaria group and 2 in the misoprostol group. In all of these cases, the excessive bleeding stopped with the use of uterotonic agents. However, definite conclusions cannot be drawn comparing major complication rates because these are relatively rare [4,5,17,18] and our study was quite small. To the best of our knowledge, only one previous prospective randomized trial compared the use of laminaria to vaginal misoprostol for cervical preparation before second-trimester D&E. In that trial, Goldberg et al. [13] compared same-day administration of 400 mcg vaginal misoprostol (given 3–4 h before D&E) to overnight laminaria in 84 women between 13 and 16 weeks of gestation. Greater preoperative dilatation was achieved with laminaria compared to misoprostol. Moreover, as opposed to our findings, procedures in the misoprostol group took longer, were more difficult and were more likely to require additional manual dilatation than those in the overnight laminaria group. Mean cervical dilation after laminaria placement was slightly lower in our trial (12.8 vs. 14.3 mm), and mean cervical dilation after misoprostol administration was slightly higher (12.4 vs. 11 mm). These differences may be explained by differences in study design; we used a shorter duration of laminaria exposure. Furthermore, we used a higher dose of misoprostol (600 mcg) and a longer duration of misoprostol exposure (11 h). While we found both laminaria and misoprostol to be effective methods for cervical preparation before secondtrimester D&E, the physician should take into consideration the risk of spontaneous expulsion of the fetus when administrating misoprostol, which may necessitate an immediate transfer to the operating room for completion. In light of this finding, as well as the increased side effects associated with misoprostol, it should be used in a monitored setting where expulsion and side effects can be managed appropriately. In different settings, laminaria might be a better choice. Our study has several limitations. First is its relatively small sample size, from which we could not draw conclusions regarding complication rates or perform a subanalysis of different outcomes. Second, our study was not blinded. This could bias the results, especially because determining the largest Hegar that can be inserted to the cervix without resistance and assessing the difficulty of the procedure are somewhat subjective. Third, we used ring forceps which are not designed for D&E as opposed to Sopher or Bierer forceps. This might affected the time needed for the procedures. Forth, we used overnight inpatient methods of cervical preparation, whereas many surgical abortions today are performed as single-day procedures at outpatient sites. In summary, our small study suggests that the efficacy of 600 mcg vaginal misoprostol given over an
extended period of time (11 h) is comparable to laminaria for cervical preparation before surgical abortions between 13 and 20 weeks of gestation. Regardless of the cervical preparation agent of choice, the majority of second-trimester abortions are not technically difficult for the experienced physician. Therefore, the decision whether to use misoprostol or laminaria for cervical preparation should take into account the uncomfortable insertion of laminaria as compared to the more frequent side effects of misoprostol, together with the experience and skill of the surgeon and, of course, the preference of the patient. Larger comparative trials are necessary to evaluate differences in complication rates.
References [1] Lohr PA, Hayes JL, Gemzell-Danielsson K. Surgical versus medical methods for second trimester induced abortion. Cochrane Database Syst Rev 2008(1):CD006714, http://dx.doi.org/10.1002/14651858.CD006714.pub2. [2] Grimes DA, Schulz KF, Cates Jr WJ. Prevention of uterine perforation during curettage abortion. JAMA 1984;251:2108–11. [3] Schulz KF, Grimes DA, Cates Jr W. Measures to prevent cervical injury during suction curettage abortion. Lancet 1983;1:1182–5. [4] Peterson WF, Berry FN, Grace MR, Gulbranson CL. Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. Obstet Gynecol 1983;62:185–90. [5] Jacot FR, Poulin C, Bilodeau AP, Morin M, Moreau S, Gendron F, et al. A five-year experience with second-trimester induced abortions: no increase in complication rate as compared to the first trimester. Am J Obstet Gynecol 1993;168:633–7. [6] Munsick RA, Fineberg NS. Cervical dilation from multiple laminaria tents used for abortion. Obstet Gynecol 1996;87:726–9. [7] Zieman M, Fong SK, Benowitz NL, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92. [8] Ho PC, Ngai SW, Liu KL, Wong GC, Lee SW. Vaginal misoprostol compared with oral misoprostol in termination of second-trimester pregnancy. Obstet Gynecol 1997;90:735–8. [9] Oppegaard KS, Abdelnoor M, Nesheim BI, Jerve F, Eskild A. The use of misoprostol for pre-abortion cervical priming: a randomized controlled trial of 400 versus 200 microg in first trimester pregnancies. BJOG 2004;111:154–9. [10] Ashok PW, Hamoda H, Nathani F, Flett GM, Templeton A. Randomized controlled study comparing oral and vaginal misoprostol for cervical priming prior to surgical termination of pregnancy. BJOG 2003;110:1057–61. [11] Todd CS, Soler M, Castleman L, Rogers MK, Blumenthal PD. Buccal misoprostol for second trimester pregnancy termination. Contraception 2002;65:415–8. [12] Maurer KA, Jacobson JC, Turok DK. Same-day cervical preparation with misoprostol prior to second trimester D&E: a case series. Contraception 2013;88:116–21. [13] Goldberg AB, Drey EA, Whitaker AK, Kang m, Meckstroth KR, Darney PD. Misoprostol compared with laminaria before early secondtrimester surgical abortion: a randomized trial. Obstet Gynecol 2005;106:234–41. [14] Grossman D, Constant D, Lince-Deroche N, Harries J, Kluge J. A randomized trial of misoprostol versus laminaria before dilation and evacuation in South Africa. Contraception 2014; 90(3):234–41.
R. Sagiv et al. / Contraception 91 (2015) 406–411 [15] Newmann SJ, Dalve-Endres A, Diedrich JT, Steiner JE, Meckstroth K, Drey EA. Cervical preparation for second trimester dilation and evacuation. Cochrane Database Syst Rev 2010(8):CD007310, http://dx.doi.org/ 10.1002/14651858.CD007310.pub2. [16] Fox MC, Krajewski CM. Cervical preparation for second-trimester surgical abortion prior to 20 weeks' gestation: SFP Guideline #2013-4. Contraception 2014;89(2):75–84.
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[17] Pridmore BR, Chambers DG. Uterine perforation during surgical abortion: a review of diagnosis, management and prevention. Aust N Z J Obstet Gynaecol 1999;39:349–53. [18] Nucatola D, Roth N, Saulsberry V, Gatter M. Serious adverse events associated with the use of misoprostol alone for cervical preparation prior to early second trimester surgical abortion (12–16 weeks). Contraception 2008;78(3):245–8.
Original research article
Laminaria vs. vaginal misoprostol for cervical preparation before second-trimester surgical abortion: a randomized clinical trial☆,☆☆ Ron Sagiv⁎, Yossi Mizrachi⁎, Hagit Glickman, Ram Kerner, Ran Keidar, Jacob Bar, Abraham Golan Department of Obstetrics and Gynecology, E. Wolfson Medical Center, Holon, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received 7 October 2014; revised 27 January 2015; accepted 27 January 2015
Abstract Objective: To compare the efficacy and tolerability of vaginal misoprostol and laminaria for cervical preparation before second-trimester surgical abortion. Study design: We performed a prospective, randomized trial comparing midnight administration of misoprostol 600 mcg vaginally to midnight placement of laminaria, before surgical abortions among women at 13–20 weeks of gestation. The primary outcome was preoperative cervical dilation. Secondary outcomes were the need for further dilation, procedure duration and difficulty, immediate complications and side effects. Results: Eighty-four women were randomized, with a median gestational age of 16.5 weeks. The mean time interval between misoprostol and laminaria placement and dilatation and evacuation initiation was 11.0±2.9 and 11.2±2.0 h, respectively (p=.17). Cervical dilation was not greater in the laminaria group as compared to the misoprostol group (12.8 vs. 12.4 mm, respectively; p=.32). No difference was demonstrated regarding the need for additional dilation or the difficulty of the procedure. Procedures performed after laminaria insertion were 1 min longer (median 11 vs. 10 min, p=.04). Participants found laminaria placement more uncomfortable than vaginal misoprostol placement. Other than pain, additional side effects occurred only in the misoprostol group, primarily nausea and vomiting. One participant in the misoprostol group experienced fetal expulsion during the night before the intended procedure. Conclusion: Either vaginal misoprostol or laminaria provides adequate dilation for second-trimester surgical abortion. Laminaria causes more pain at insertion and misoprostol causes more side effects. Implications statement: We found that cervical preparation in an inpatient setting for approximately 11 h with misoprostol 600 mcg vaginally is comparable to 11 h of laminaria. However, given the potential for spontaneous expulsion and more side effects with misoprostol, laminaria is likely a better general option in such a setting. © 2015 Elsevier Inc. All rights reserved. Keywords: Cervical preparation; Misoprostol; Laminaria; Surgical abortion
1. Introduction Dilatation and evacuation (D&E) is the most common mode of second-trimester elective abortion in the United States [1]. Cervical preparation before D&E is essential to
☆
Financial disclosure: No potential conflicts of interest for any of the authors. ☆☆ Clinical trial registration: http://clinicaltrials.gov/show/NCT01678703. ⁎ Corresponding authors. Department of Gynecology & Obstetrics, E. Wolfson Medical Center, 62 Halochamim Street, Holon 58100, Israel. Tel.: + 972 3 502 8329; fax: + 972 3 502 8503. E-mail address: [email protected] (R. Sagiv). http://dx.doi.org/10.1016/j.contraception.2015.01.018 0010-7824/© 2015 Elsevier Inc. All rights reserved.
minimize complications such as cervical trauma, uterine perforation and excessive bleeding [2–6]. The cervix may be prepared with pharmacological agents such as misoprostol, or with mechanical agents such as laminaria. Vaginal, oral or buccal administration of misoprostol has proven successful for cervical preparation in first- and second-trimester surgical abortion. Overall, vaginal administration results in more consistent absorption and better cervical dilation than oral administration [7–12]. Several studies compared the efficacy of misoprostol and osmotic dilators for cervical preparation prior to secondtrimester D&E. A previous randomized trial [13] compared the administration of same-day 400 mcg vaginal misoprostol to overnight laminaria before early second-trimester surgical
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abortion. Participants who underwent preparation with laminaria were found to have greater dilatation at the time of the procedure. Moreover, procedures took longer and were technically more challenging after cervical preparation with same-day misoprostol. A second randomized trial [14] compared the efficacy of same-day 400 mcg buccal misoprostol to laminaria inserted the day before D&E among women at 13–19 weeks of gestation. Both regimens were found to have similar low rates of adverse effects. Misoprostol participants were more likely to require additional mechanical dilation. A Chocrane Database Systemic Review [15] assessed all available randomized trials of cervical preparation prior to second trimester D&E. Cervical preparation with osmotic dilators and/or misoprostol was found to be safe and effective. Osmotic dilators appeared to provide superior cervical dilation; however, this difference in cervical dilation did not appear to result in differences in procedure time or complication rates. The Society of Family Planning (SFP) [16] states that the use of misoprostol as an alternative to osmotic tents increases the risk of inadequate cervical dilation. It recommends that only experienced providers capable of managing difficult cervical dilation should use protocols omitting osmotic tent placement prior to D&E. However, the SFP examined only studies that used a short same-day regimen of misoprostol. Our objective was to compare extended administration of 600 mcg vaginal misoprostol with placement of laminaria for cervical preparation before second-trimester surgical abortion.
2. Materials and methods We performed a prospective, unblinded, randomized (1:1) study in 84 patients who underwent D&E for termination of pregnancy at 13–20 weeks of gestation. The study was performed from January 2008 to January 2011 at the Edith Wolfson Hospital in Holon, Israel. The study protocol was approved by the institutional review board. Patients were referred to have surgical termination of pregnancy, and these were performed according to Israeli law after approval from a pregnancy termination committee. Eligible participants were all at least 15 years old and in good general health. Gestational age was confirmed by first-trimester ultrasound examination. Exclusion criteria were allergy to misoprostol, fetal demise, bleeding disorder, current anticoagulation therapy, previous loop electrosurgical excision procedure or conization procedure, multiple gestation and breast-feeding. Patients with previous cesarean scar were not excluded. All participants were hospitalized the day before the procedure. Subjects were randomly assigned to cervical preparation with either misoprostol or laminaria. Randomization was performed using a computer-generated list of random numbers by a researcher not involved in subject recruitment or care. Treatment allocation was concealed by placing assignments in sequentially numbered opaque
407
envelopes. After providing a written informed consent, a research assistant opened the envelope and notified the physician performing the subject's preoperative evaluation of treatment assignment. Participants randomized for laminaria had them placed at midnight before the procedure. The vagina was cleansed with aqueous Betadine® solution. The direction of the cervix was noted, and one to six laminaria tents were placed within the cervical canal using a tenaculum applied to the cervix. The number of laminaria tents was determined by the clinician. Paracervical anesthesia was not performed. Participants assigned for misoprostol had three 200-mcg tablets (a 600-mcg dose) administered vaginally to the posterior fornix at midnight. Subjects who had vaginal bleeding or expulsion of the fetus during the night before the intended procedure were evaluated and, when indicated, transferred immediately to the operating room to complete the evacuation. For the procedure, all subjects received general endotracheal anesthesia. Procedures were performed by four physicians, all of whom had more than 10 years of experience performing D&Es. The operating physicians were not blinded to the treatment arm. The operating physician placed a speculum and then assessed initial cervical dilation by gradual insertion of Hegar dilators, noting the largest dilator that fit through the cervix without resistance. Timing of the procedure was started with the onset of either additional rigid dilation, when required, or introduction of a forceps or suction cannula. Ring forceps were used for the procedures. Procedure time was ended when the last instrument was removed from the uterus. Procedures were performed under ultrasound guidance. Subjects were discharged when medically stable 6–8 h after the procedure. Upon completion of the procedure, the operating physician was asked to rate the difficulty of the procedure on a 5-point Likert scale, defined as: 0=no difficulty, 1=mild difficulty, 2=mild to moderate difficulty, 3=moderate difficulty, 4=moderate to marked difficulty and 5=marked difficulty. Adverse effects were assessed with a series of questionnaires. Pain was assessed using the VAS score (ranging from 1=no pain to 10=the worst possible pain), ranked by the participants at various time periods: immediately after laminaria or misoprostol placement, 3 to 4 h after laminaria or misoprostol placement, and upon discharge from the department. Pain control management was similar in both groups. Upon request, participants were given 1 g dipyrone (Optalgin®) orally. Participants requesting additional analgesia received 75 mg diclofenac (Voltaren®) intramuscularly. If needed, additional dose of dipyrone was given after 6 h, and additional dose of diclofenac was given after 8 h. Other adverse effects were reported by the participants 3 to 4 h after laminaria or misoprostol placement using a yes or no questionnaires. Subjects' demographics, reproductive history and complications were abstracted from the medical record.
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The primary outcome was preoperative cervical dilatation. Secondary outcomes were the need for further dilation, procedure duration and difficulty, side effects and immediate complications. Post hoc sample size calculations showed that with 30 women in each group, the study had 80% power to distinguish a true, between-group difference of 2 mm (SD 2.7 mm) in preoperative vaginal dilation, with a 2-sided alpha of .05. We assumed that a difference less than 2 mm lacks clinical significance. Data were analyzed on SPSS v21.0 statistical analysis software (IBM Inc., USA). Distributions of continuous variables were assessed for normality using the Kolmogorov– Smirnov test (cutoff at pb.1). Normally distributed continuous outcomes were compared by using the two-tailed t test. Continuous variables that were not normally distributed were compared by using the Mann-Whitney U test. Nominal
variables were compared by group using the chi-square test and Fisher's Exact Test as needed. All tests were two sided and considered significant at pb.05. 3. Results A total of 117 women seeking surgical abortion services between 13 and 20 weeks of gestation were assessed for eligibility during the study period, and 84 women were enrolled (Fig. 1). Forty-one subjects were assigned to the misoprostol group, and 43 subjects were assigned to the laminaria group. All participants completed the study and were evaluated. There were no differences in demographic or clinical characteristics between groups (Table 1). The mean number of laminaria inserted in the laminaria group was 3.5±1.9. The mean time interval between laminaria or misoprostol
CONSORT 2010 Flow Diagram
Enrollment
Assessed for eligibility (n=117)
Excluded (n=33) Not meeting inclusion criteria (n=27) Declined to participate (n=6) Other reasons (n=0)
Randomized (n=84)
Allocation Allocated to misoprostol (n=41) Received allocated intervention (n=41)
Allocated to laminaria (n=43) Received allocated intervention (n=43)
Did not receive allocated intervention (n=0)
Did not receive allocated intervention (n=0)
Follow-Up Lost to follow-up (n=0)
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Discontinued intervention (n=0)
Analysis Analysed (n=41) Excluded from analysis (n=0)
Analysed (n=43) Excluded from analysis (n=0)
Fig. 1. CONSORT flowchart.
R. Sagiv et al. / Contraception 91 (2015) 406–411
placement and D&E initiation was 11.2±2.0 and 11.0±2.9 h, respectively (p=.17). Preoperative cervical dilation did not differ between laminaria and misoprostol groups (12.8 vs. 12.4 mm, respectively; p=.32) (Table 2). Procedures performed after laminaria insertion were 1 min longer than those performed after misoprostol insertion (median of 11 min vs. 10 min, respectively; p=.04). The proportion of cases that required additional dilation and the median level of difficulty of the procedure did not differ between the two groups (Table 2). The majority of the procedures in both groups were rated as either not difficult or mildly difficult. All procedures were completed on a single attempt in both groups. Data regarding pain with cervical preparation administration, during the time between administration and procedure and upon discharge are presented in Table 3. Other than pain, side effects occurred with a frequency of between 2% and 15% only in the misoprostol group, with nausea and vomiting being significantly more frequent (Table 3). In the misoprostol group, one participant experienced uterine bleeding and expulsion of the fetus during the night before the intended procedure. She was transferred immediately to the operating room to complete the evacuation. Gestational age was 13 weeks and 4 days. In five other participants, the fetus was found to be bulging into the vagina upon initiation of the procedure. Fetuses were fully extracted using the ring forceps or by fundal pressure, and the procedures were completed by curettage. Three cases of excessive bleeding during or immediately after the procedure were noted. One case occurred in the laminaria group, necessitated transfusion of 2 units of packed red blood cells. The other two cases of bleeding were in the misoprostol group. The etiology of bleeding was assumed uterine atony in all cases. Subjects were treated with oxytocin and the bleeding ceased with no need for further intervention. 4. Discussion In this small prospective randomized trial, we found that both misoprostol and laminaria placed at midnight are similarly effective for cervical preparation before secondtrimester D&E. No difference was found regarding preoperative cervical dilatation, the need for further dilatation or the difficulty of the procedure. Table 1 Baseline characteristics of the misoprostol and laminaria groups
Age (years) Gestational age (weeks) Nulliparous Previous vaginal deliveries Previous cesarean deliveries
Misoprostol group (n=41)
Laminaria group (n= 43)
p
30 (15–47) 17 (14–20) 21 (51.2%) 15 (36.5%) 6 (14.6%)
29 (17–45) 16 (14–20) 23 (53.4%) 18 (41.8%) 4 (9.3%)
.89 .86 .88 .7 .47
Data are presented as median (range) or n (%).
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Table 2 Clinical outcomes among subjects randomized to laminaria vs. misoprostol for cervical preparation before second-trimester abortion
Interval between misoprostol/laminaria placement and initiation of the procedure (h) Mean initial dilation (mm) Median procedure duration (min) Additional dilation required Median difficulty of procedure (0–5 scale)
Misoprostol (n=41)
Laminaria (n= 43)
p
11.0±2.9
11.2±2.0
.17
12.4±2.7 10 (3–20) 12 (30%) 1 (0–4)
12.8±1.8 11 (5–30) 14 (32%) 1 (0–4)
.32 .03 .8 .4
Data are presented as mean (±standard deviation) or median (range).
Procedures performed after laminaria insertion were 1 min longer. This can be explained by the fact that in the misoprostol group, there were five cases in which the fetus was found to be bulging into the vagina upon initiation of the procedure and was fully extracted using the ring forceps or by fundal pressure. These procedures were later completed only by curettage and therefore were shorter. However, we believe that this small difference in procedure duration lacks clinical importance. Participants found laminaria placement more uncomfortable than misoprostol placement. We assume that the pain related to laminaria insertion is due to grasping of the cervix with the tenaculum and introduction of laminaria tents into the cervical canal. These painful steps are not required while placing misoprostol tablets in the vagina. We did not use cervical anesthesia, which may decrease pain with laminaria insertion. Moreover, paracervical anesthesia might enable the insertion of more laminaria and achievement of wider dilatation. Although the initial cervical dilation and procedure duration and difficulty are important measures of efficacy to consider when selecting a cervical preparation method,
Table 3 Subjects' assessments of adverse effects of misoprostol and laminaria before second-trimester abortion Misoprostol Laminaria p (n= 41) (n=43) Pain a With laminaria or misoprostol placement 1 (1–6) During the night before surgical abortion 5.5 (1–10) After the procedure 1 (1–5) Nausea 6 (15%) Vomiting 5 (12%) Diarrhea 1 (2%) Chills 2 (5%) Fever 2 (5%)
4 (1–10) 3 (1–10) 2 (1–10) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
b.001 .08 .2 .01 .02 .4 .2 .2
Data are presented as median (range) for pain and n (%) for other outcomes. a Visual analog scale, scored from 1 to 10.
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differences in complication rates are also of a great importance. In our study, there were three cases of bleeding during or immediately after the procedure: one case in the laminaria group and 2 in the misoprostol group. In all of these cases, the excessive bleeding stopped with the use of uterotonic agents. However, definite conclusions cannot be drawn comparing major complication rates because these are relatively rare [4,5,17,18] and our study was quite small. To the best of our knowledge, only one previous prospective randomized trial compared the use of laminaria to vaginal misoprostol for cervical preparation before second-trimester D&E. In that trial, Goldberg et al. [13] compared same-day administration of 400 mcg vaginal misoprostol (given 3–4 h before D&E) to overnight laminaria in 84 women between 13 and 16 weeks of gestation. Greater preoperative dilatation was achieved with laminaria compared to misoprostol. Moreover, as opposed to our findings, procedures in the misoprostol group took longer, were more difficult and were more likely to require additional manual dilatation than those in the overnight laminaria group. Mean cervical dilation after laminaria placement was slightly lower in our trial (12.8 vs. 14.3 mm), and mean cervical dilation after misoprostol administration was slightly higher (12.4 vs. 11 mm). These differences may be explained by differences in study design; we used a shorter duration of laminaria exposure. Furthermore, we used a higher dose of misoprostol (600 mcg) and a longer duration of misoprostol exposure (11 h). While we found both laminaria and misoprostol to be effective methods for cervical preparation before secondtrimester D&E, the physician should take into consideration the risk of spontaneous expulsion of the fetus when administrating misoprostol, which may necessitate an immediate transfer to the operating room for completion. In light of this finding, as well as the increased side effects associated with misoprostol, it should be used in a monitored setting where expulsion and side effects can be managed appropriately. In different settings, laminaria might be a better choice. Our study has several limitations. First is its relatively small sample size, from which we could not draw conclusions regarding complication rates or perform a subanalysis of different outcomes. Second, our study was not blinded. This could bias the results, especially because determining the largest Hegar that can be inserted to the cervix without resistance and assessing the difficulty of the procedure are somewhat subjective. Third, we used ring forceps which are not designed for D&E as opposed to Sopher or Bierer forceps. This might affected the time needed for the procedures. Forth, we used overnight inpatient methods of cervical preparation, whereas many surgical abortions today are performed as single-day procedures at outpatient sites. In summary, our small study suggests that the efficacy of 600 mcg vaginal misoprostol given over an
extended period of time (11 h) is comparable to laminaria for cervical preparation before surgical abortions between 13 and 20 weeks of gestation. Regardless of the cervical preparation agent of choice, the majority of second-trimester abortions are not technically difficult for the experienced physician. Therefore, the decision whether to use misoprostol or laminaria for cervical preparation should take into account the uncomfortable insertion of laminaria as compared to the more frequent side effects of misoprostol, together with the experience and skill of the surgeon and, of course, the preference of the patient. Larger comparative trials are necessary to evaluate differences in complication rates.
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