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Misoprostol Compared With Laminaria Before Early Second-Trimester Surgical Abortion: A Randomized Trial

Goldberg, Alisa B. MD, MPH; Drey, Eleanor A. MD, EdM; Whitaker, Amy K. MD; Kang, Mi-Suk MPH; Meckstroth, Karen R. MD, MPH; Darney, Philip D. MD, MSc

doi: 10.1097/01.AOG.0000168629.17326.00
Original Research
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Objective: To compare the efficacy and acceptability of same-day misoprostol and overnight laminaria for cervical ripening before early second-trimester surgical abortion.

Methods: We performed a randomized, double-blinded, controlled trial comparing 400 μg of vaginal misoprostol, given 3–4 hours preoperatively, with overnight laminaria before early second-trimester surgical abortion among women at 13.0–16.0 weeks of gestation (n = 84). The primary outcome was procedure time, and the sample size was based on 95% power to detect a difference of 4.5 minutes between groups. Secondary outcomes included completion of the procedure on the first attempt, procedural difficulty, and patients' pain scores and preferences.

Results: The average gestational duration was 14 weeks 6 days. Procedures performed after laminaria were significantly faster than those after misoprostol (median 3.4 versus 7.2 minutes, respectively, P = .01). Laminaria patients had significantly greater dilation than misoprostol patients at abortion (mean 43 versus 33 French, P < .001), and more misoprostol patients required additional dilation (85% versus 21%, P < .001). Physicians rated 27% of the misoprostol procedures as moderate-markedly difficult versus 5% of laminaria procedures (P = .01). Differences in efficacy were pronounced among nulliparous patients. There were no significant differences in ability to complete the procedure on the first attempt or patients' intraoperative pain scores. More women in the misoprostol group would choose their assigned method again (93% versus 62%, P < .01), and 82% of all subjects preferred a 1-day procedure.

Conclusion: Early second-trimester abortions take longer and are technically more challenging after cervical ripening with same-day misoprostol than with overnight laminaria, but patients prefer same-day misoprostol.

Level of Evidence: I

Early second-trimester abortions are technically more challenging and take longer after cervical ripening with same-day misoprostol than after overnight laminaria, especially among nulliparas.

From the Department of Obstetrics and Gynecology Brigham and Women's Hospital and Harvard Medical School and Planned Parenthood League of Massachusetts Inc, Boston Massachusetts; and the Department of Obstetrics, Gynecology, and Reproductive Sciences and the Center for Reproductive Health Research and Policy, San Francisco General Hospital, University of California, San Francisco, California.

See related editorial on page 216.

Financial support for this study was received from the University of California San Francisco Center for Reproductive Health Research and Policy.

Corresponding author: Alisa B. Goldberg, MD, MPH, Planned Parenthood League of Massachusetts Inc, 1055 Commonwealth Avenue, Boston, MA 02215; Alisa_Goldberg@pplm.org.

Cervical ripening before surgical abortion is an effective method for reducing the complications associated with suction curettage.1,2 Although not always used before first-trimester surgical abortion, where the absolute risk of complications is low, cervical ripening is routine before second-trimester dilation and evacuation (D&E). Preoperative treatment with laminaria, a hydrophilic dilator, has been the standard method of cervical preparation before D&E for many years. Laminaria are highly effective for this indication,3 but insertion can be associated with discomfort for the patient,4 and laminaria are not available in many countries. In addition, because laminaria work optimally when left in place overnight,5 their use requires that abortions be completed as a 2-day procedure. Many women in the United States and around the world have limited access to second-trimester abortion services and must travel long distances to receive care.6 Women traveling many hours to have a 2-day procedure frequently must spend the night away from home, which may present a significant obstacle for women with limited resources. Similarly, in addition to the costs of the laminaria themselves, 2-day procedures may engender higher costs to the health care system and require additional child care arrangements and time off from work for patients.

Cervical ripening can also be achieved by pharmacological means (eg, prostaglandins or mifepristone), and there is a growing body of literature supporting the use of misoprostol, an inexpensive widely available synthetic prostaglandin E1 analogue, for cervical ripening before first-trimester aspiration abortion.4,7–9 Misoprostol given vaginally is more effective than oral administration for cervical ripening before first-trimester suction abortions4 and is associated with fewer adverse effects.10 In a randomized, double-blinded study of 120 women undergoing cervical ripening before first-trimester abortion, the vaginal dose with the best efficacy and adverse-effect profile was found to be 400 μg.11 The same investigators carried out a randomized, double-blinded study of 180 women to determine the most appropriate interval between misoprostol administration and surgery. An interval of 3 hours with a dose of 400 μg was significantly more effective in achieving adequate dilation with fewer adverse effects than a 2-hour interval with either 600 μg or 800 μg.12

Although there are many randomized trials demonstrating the efficacy of misoprostol for second-trimester pregnancy termination by induction of labor,13–16 there is very little published evidence supporting the use of misoprostol alone for cervical ripening before early second-trimester surgical abortion. We identified only one study of misoprostol for this purpose. This retrospective study reported adequate cervical preparation in all women (n = 32) who received 600 μg of misoprostol administered buccally 2–4 hours before D&E at 14–16 weeks of gestation. Procedure time was found to be comparable to women at 16–18 weeks of gestation who had cervical ripening with laminaria (n = 78).17 Despite scant published evidence, misoprostol is used commonly before early second-trimester abortions with no standardized method for doing so. We, therefore, compared same-day misoprostol with overnight laminaria for cervical ripening before early second-trimester surgical abortion in a randomized, double-blinded trial.

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MATERIALS AND METHODS

For our double-blinded, randomized trial, we recruited English- or Spanish-speaking women who were in good health, at least 18 years old, between 12 weeks 6 days of gestation and 15 weeks 6 days of gestation by ultrasound examination, and sure of their decision to have an outpatient pregnancy termination at San Francisco General Hospital. All women were recruited on the day before their procedure, so all abortions were completed between 13 and 16 weeks of gestation. Enrollment took place between February 2002 and September 2003. Women were excluded if they had more than one prior cesarean delivery, a multiple gestation, a fetal demise confirmed by ultrasound examination, a documented cervical or lower uterine segment myoma measuring more than 3 cm in diameter, a history of prior cone biopsy or loop electrosurgical excision procedure, a bleeding disorder or current anticoagulation therapy, an intrauterine device in place, an allergy to misoprostol, or if they were breastfeeding and were unwilling to temporarily discard milk. Our primary outcome was procedure time, with secondary outcomes including cervical dilation at the start of the abortion procedure, difficulty of further dilation if required, overall procedural difficulty, ability to complete the procedure on the first attempt, and subject acceptability, including pain scores, adverse effects, and preferences. Our study was approved by the Committee on Human Research of the University of California, San Francisco.

After giving written informed consent, subjects were randomly assigned to cervical preparation with either misoprostol or laminaria. A blocked randomization scheme was created from a computer-generated random numbers table by a researcher not involved in subject recruitment or patient care. Treatment allocation was concealed by placing assignments in sequentially numbered opaque envelopes. After enrollment, a research assistant opened the envelope and notified the physician or nurse practitioner performing the subject's preoperative evaluation of treatment assignment. To double-blind the treatment assignment, the patient was not informed of her group and the nurse practitioners and physicians who placed the cervical ripening agent did not perform the abortion on that patient. At the time of preoperative evaluation, all women underwent a speculum examination and screening for Chlamydia and gonorrhea. During the examination a script was read to each patient, which explained that she might feel pinching and cramping. All women who were randomized to the laminaria group had a paracervical block with 10 mL of chloroprocaine and then had 3–6 medium laminaria (4 mm size, Berkeley Medevices Inc, Richmond, CA) placed within the cervical canal. Women assigned to the misoprostol arm also underwent a speculum examination and the same script was read, but no injections were given and no dilators were placed. All patients were then discharged from clinic and instructed to return the following day for their scheduled procedures.

On the day of the procedure, all women underwent a digital examination. Each woman randomized to the misoprostol group had two 200-μg tablets (a 400-μg dose) placed in the posterior fornix of her vagina. Each woman randomized to the laminaria group had 2 placebo tablets (vitamin B6) placed in the posterior fornix of her vagina. Tablets were moistened with 2–3 drops of saline before insertion. All subjects then waited in the clinic for 3–4 hours until their procedure. After the waiting period, women were taken to the procedure room and the nonoperating physician who placed the tablets earlier that day removed all laminaria, sponges, and tablets, placed the speculum, and prepared the cervix with povidone-iodine, per standard clinic protocol. After this was completed, the operating physician entered the procedure room. Operating physicians, all attending gynecologists, had introduced themselves to subjects previously but were not present for administration or removal of the cervical ripening agents.

All patients received intravenous moderate sedation with fentanyl and midazolam and a 20-mL paracervical block, according to routine clinic protocol. Before beginning the procedure, the operating physician measured cervical dilation using Pratt dilators. Measurement was done by starting with a 53 Pratt dilator and sequentially attempting to pass smaller dilators to identify the largest dilator that would pass without resistance. We measured from largest to smallest to prevent dilation with the measurement procedure. Once measurement was complete, a stopwatch was used to begin timing the procedure, which began either with mechanical dilation, when required, or with the introduction of the suction cannula. Additional dilation, if needed, was achieved using Pratt dilators, and the pregnancy was removed by a combination of suction curettage using a 14-mm cannula (the largest available in our clinic) and forceps, if necessary, according to routine clinic protocol. The timer was stopped when the final instrument was removed from the cervix. All procedures were done under ultrasound guidance. If dilation was inadequate to complete the procedure on the first attempt, further management was left to the discretion of the operating physician.

After the abortion, a brief questionnaire was administered to the operating physician to subjectively assess procedural difficulty. For those patients who required additional dilation, physicians were asked to rate the difficulty of the dilation on a 5-point Likert scale, defined as 0 = not difficult, 1 = mildly difficult, 2 = between mild and moderately difficult, 3 = moderately difficult, 4 = between moderately and markedly difficult, and 5 = markedly difficult. Physicians used the same scale to subjectively rate overall procedural difficulty. Pain, adverse effects, and subject acceptability were assessed with a series of 4 questionnaires administered to subjects: after the initial examination and laminaria placement, upon arrival on the procedure day, after the 3- to 4-hour waiting period, and upon discharge from the clinic after the abortion procedure. Pain was assessed by using a 5-point Likert scale and adverse effects were measured in an ordinal fashion based on severity, then dichotomized for analysis. Additional data about the procedure, subject demographics, reproductive history, and complications were abstracted from the medical record immediately after the procedure. The adequacy of blinding was assessed by having both subjects and operating physicians guess treatment group assignment and then comparing their guesses with actual assignments.

In the absence of published trial data to help us determine sample size, we collected 3 months of clinical data on procedure times for abortions done between 13 and 16 weeks of gestation at our institution. We found that procedures completed after laminaria took a mean of 5.6 minutes (± 3.2 minutes), and procedures after misoprostol took a mean of 10.1 minutes (± 5.2 minutes). Using a 2-tailed hypothesis with an alpha error of 0.05 and 95% power, we calculated that we would need a total of 78 patients to detect a 4.5-minute difference between groups. Six additional pilot patients were recruited, with a plan to include their data in the analyses if study procedures did not change significantly after completion of the pilot patients. All data were entered into Microsoft Access (Redmond, WA) and imported into STATA 7.0 (College Station, TX) for analysis. Normally distributed continuous outcomes were compared by using the 2-tailed Student t test. Continuous outcomes that were not normally distributed were compared by using a nonparametric 2-sample test for equality of medians, and binary outcomes were compared using the χ2 and Fisher exact tests. A kappa statistic was used to evaluate the efficacy of our blinding procedure by comparing actual group assignment with subjective assessment of group assignment.

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RESULTS

A total of 203 women seeking abortion services between 13 and 16 weeks of gestation were assessed for eligibility; 131 were eligible to participate, and 84 women enrolled during the 20 months of recruitment (Fig. 1). Although the first 6 subjects enrolled were pilot subjects, no significant changes were made to the protocol after their enrollment, and their data were included in the analysis. One subject was excluded after randomization because she did not return for her abortion procedure on day 2. She was in the misoprostol arm and had not received any cervical ripening agent on day 1. Analysis is presented for the remaining 83 women. There were no statistically significant differences in demographic or clinical characteristics between groups (Table 1). Women had a mean gestational age of 14 weeks 6 days. Most women were black or Latina and had state-funded insurance (Medi-Cal). Thirty-one percent of women were nulliparous, 52% had at least one prior vaginal delivery, and 24% had one prior cesarean delivery.

Fig

Fig

Table 1

Table 1

Women who received laminaria had significantly more dilation at the time of abortion than those who received misoprostol (Table 2). To complete the procedure, 80% of misoprostol subjects required additional dilation with Pratt dilators, compared with 21% of laminaria subjects (P < .001). Thirty-four percent of misoprostol procedures were completed with suction curettage alone versus 26% of laminaria procedures (P = .43). Procedures performed after misoprostol took significantly longer than those after laminaria (Table 2). Although the additional dilation required for misoprostol patients was significantly more difficult than the additional dilation required for laminaria patients, in the majority of cases additional dilation was either not difficult or only mildly difficult (Table 3). Overall, physicians rated procedures after misoprostol as significantly harder than procedures after laminaria (27% of misoprostol procedures received a difficulty score of 3 or greater versus 5% of laminaria procedures, P < .01; Table 3). However, the majority of procedures in both groups were rated as either not difficult or mildly difficult. All procedures could be completed on the first attempt after laminaria, but one procedure in the misoprostol group could not be completed on the first attempt (Table 2). In this case, a nullipara at 13 weeks 5 days of gestation, a second dose of misoprostol was administered buccally, and the procedure was reattempted 3 hours later. On the second attempt, the procedure was able to be completed without complication, but procedure time was prolonged (17.9 minutes), and the case was rated as markedly difficult.

Table 2

Table 2

Table 3

Table 3

Looking separately at nulliparous patients (n = 26), our findings are more striking. Median procedure time was 9.5 minutes (range 3.2–18.3) for nulliparous women who received misoprostol, compared with 3.4 minutes (range 1.2–20.9) for those in the laminaria group (P < .001). The median overall procedural difficulty score among nulliparas was 2 for women in the misoprostol group, compared with 0 for women in the laminaria arm (P < .001), and all nulliparous women whose procedure was rated as moderate to severely difficult (n = 6) had received misoprostol (P = .007). Although trends were similar among parous women, there were no statistically significant differences in procedure time, overall procedural difficulty, or percentage of women with moderate-to-severely-difficult procedures, whether parous women received cervical preparation with misoprostol or laminaria.

There were 3 complications in the misoprostol group: one uterine perforation in a nulliparous woman at 15 weeks 6 days of gestation and 2 cervical lacerations not requiring suturing in parous subjects at 13 weeks 1 day and 14 weeks 5 days of gestation. There were 2 complications in the laminaria group: one case of endometritis and one uterine reaspiration, both in parous women at 15 weeks 6 days and 15 weeks 1 day gestation, respectively. In all of these cases except the patient at 13 weeks of gestation, forceps were used to complete the procedure.

Subjects found laminaria placement significantly more uncomfortable than the speculum examination with sham placement, and laminaria patients had significantly more discomfort overnight between day 1 and day 2 (Table 4). However, during the 3- to 4-hour waiting period, misoprostol patients had significantly more discomfort than laminaria patients (Table 4). Intraoperative pain control was similar between the groups (Table 4), as was recollection of the procedure (68% of misoprostol subjects and 67% of laminaria subjects reported remembering most or all of the procedure, P = .87). There was no difference in the frequency of nausea, vomiting, or diarrhea between groups, but misoprostol patients had more chills during the 3- to 4-hour waiting period (Table 4). Overall, 93% of subjects in both groups were either satisfied or very satisfied with the care they received for their abortion procedure, yet significantly more women who were randomized to misoprostol would choose their assigned method again (93% versus 62% of laminaria patients, P = .001). Regardless of group assignment, 82% of all subjects said they preferred to have a 1-day procedure with misoprostol than a 2-day procedure with laminaria.

Table 4

Table 4

Although blinding was imperfect, it was effective in many cases. If blinding were perfect, guesses would reflect chance alone, and each group would guess correctly approximately 50% of the time. Physicians guessed correctly for 70% of subjects (kappa = 0.45, P < .001). Subjects guessed correctly 60% of the time (kappa = 0.36, P < .001). Group assignment influenced the success of blinding for subjects, but not for physicians. Women in the misoprostol group were more successful at guessing their treatment arm correctly than women in the laminaria group (78% of misoprostol subjects guessed correctly versus 43% of laminaria subjects, P = .001), and physicians were just as likely to guess correctly regardless of treatment arm (74% for laminaria subjects versus 66% for misoprostol subjects, P = .43).

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DISCUSSION

Cervical ripening before early second-trimester surgical abortion is essential to minimize cervical trauma and the risk of uterine perforation,1 but the ideal method of cervical ripening before early second-trimester abortion is unknown.

We found that procedures performed after misoprostol took significantly longer and were technically more challenging than procedures done after cervical ripening with laminaria. Misoprostol procedures were significantly more likely to be rated as moderately-to-severely difficult. These effects were particularly striking among nulliparous women and not statistically significant among parous women. Despite these differences, the majority of procedures in both groups were rated as either not difficult or only mildly difficult. This suggests that, although the majority of early second-trimester abortions are straightforward regardless of cervical ripening method, problematic cases are more likely after misoprostol. Differences in the efficacy of these 2 methods of cervical ripening may be of less clinical importance at the lower end of our gestational age range, where procedures can be completed with suction curettage alone, than at the upper limit, where forceps may be required to complete the procedure. However, we did not have adequate sample size to address this hypothesis.

For this trial, we chose a misoprostol regimen with a dose, route, and interval proven effective for cervical ripening before first-trimester suction curettage. Although we found this regimen also to be effective for cervical ripening before second-trimester surgical abortion, it was less effective than overnight laminaria. Our study does not address the relative efficacy of other doses and routes of misoprostol administration. Nor does it address the ideal preoperative interval required to achieve maximum cervical ripening effect from misoprostol in the second trimester. Although alternative regimens are also likely to ripen the cervix in the second trimester, additional trials are required to assess how other regimens compare with overnight laminaria.

Although procedure time, initial dilation, and procedural difficulty are important measures of efficacy to consider when selecting a cervical ripening method, differences in complication rates are of the utmost importance. The 1 uterine perforation and 2 cervical lacerations in the misoprostol group are of concern, as is the increased level of difficulty with misoprostol preparation and the increased need for mechanical dilation in these patients. Despite our concern, we cannot draw conclusions comparing complication rates between these methods of cervical ripening. To detect a difference in uterine perforation rate from a reported baseline of 0.32%18 to 1% with an alpha error of 0.05 and 80% power, we would have required 2,511 women in each arm of the study.

With regard to subjects' experiences, we found that women had equivalent and mild discomfort with both ripening methods. The only difference was the time at which discomfort occurred. Laminaria subjects had discomfort during placement and overnight, and misoprostol subjects had discomfort during the 3-hour waiting period. There was no difference in pain during procedures; all patients were fairly comfortable with intravenous moderate sedation. However, our assessment of intraoperative pain was limited by the fact that measurements were taken postoperatively. Adverse effects of both ripening methods were mild and similar, except that misoprostol patients had more chills during the preoperative waiting period. Overall, all subjects greatly preferred to have a 1-day procedure with misoprostol instead of a 2-day procedure with laminaria.

Strong patient preference for a 1-day procedure and serious limitations with access to second-trimester abortion services may be the primary factors influencing providers to use same-day misoprostol as a cervical ripening agent before early second-trimester surgical abortion. Our study suggests that 400 μg of vaginal misoprostol given 3–4 hours preoperatively is inferior to overnight laminaria for cervical ripening before surgical abortion between 13 and 16 weeks of gestation. The difference in efficacy appears to have little clinical significance among parous women but has a substantial effect among nulliparous women. Regardless of ripening agent, the majority of early second-trimester abortions will not be technically difficult for experienced providers. Given these findings, the decision of whether to use same-day misoprostol or overnight laminaria for cervical ripening between 13 and 16 weeks of gestation should take into account parity, the likelihood that the procedure will be able to completed with suction curettage alone, the experience and skill of the surgeon, and a careful preoperative clinical assessment of other factors that might affect procedural difficulty. Whether other misoprostol regimens or a combination of misoprostol and osmotic dilators for a same-day procedure can achieve a comparable effect to overnight laminaria needs to be investigated. Much larger comparative trials are necessary to evaluate differences in complication rates.

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REFERENCES

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© 2005 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.