Obstetrics & Gynecology:
Self-Administered Misoprostol or Placebo Before Intrauterine Device Insertion in Nulliparous Women: A Randomized Controlled Trial
Swenson, Carolyn MD; Turok, David K. MD, MPH; Ward, Katherine DNP, WHNP; Jacobson, Janet C. MD; Dermish, Amna MD
From the Departments of Obstetrics and Gynecology, University of Utah, and University of Utah College of Nursing, Salt Lake City, Utah.
The authors thank their colleagues at the University of Utah Family Planning Research Group, including Patricia Murphy and Kirtly Jones, for editorial support.
Presented as an oral presentation at the North American Forum on Family Planning, October 22–24, 2011, Washington, DC.
Corresponding author: Carolyn Swenson, MD, University of Utah, Department of Obstetrics and Gynecology, 30N 1900E, Suite 2B200, Salt Lake City, UT 84132; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVES: To estimate the effects of self-administered misoprostol compared with placebo before intrauterine device (IUD) insertion in nulliparous women.
METHOD: Nulliparous women requesting either the copper T380A or levonorgestrel IUD were randomized to self-administer either 400 μg of misoprostol or placebo (vaginally or buccally) 3–4 hours before the IUD insertion appointment. The primary outcome was health care provider–perceived ease of insertion recorded on a visual analog scale (anchors: 0 extremely easy, 100 impossible). Patients completed questionnaires addressing pain using a validated visual analog scale (anchors: 0 none, 100 worst imaginable) before insertion, immediately postinsertion, and before clinic discharge.
RESULTS: Of the 108 women enrolled in the study, 54 received misoprostol and 54 received placebo. There was no significant difference in perceived ease of insertion between the two groups (25.0 mm [standard error 3.5] compared with 27.4 mm [standard error 3.5], P=.64). Patients who received misoprostol before IUD insertion had significantly higher pain scores before placement (17.1 mm [standard error 3.5] compared with 4.7 mm [standard error 2.0], P=.003). Groups did not differ in perception of pain during IUD insertion (58.4 mm [standard error 3.3] compared with 56.9 mm [standard error 3.0], P=.74). There were two expulsions in the misoprostol group and none in the placebo group. Failed insertions, need for adjuvant pain medication, and need for cervical dilation or ultrasonographic guidance did not differ between the two groups.
CONCLUSION: Self-administered misoprostol before IUD insertion does not ease IUD insertion or reduce patient-perceived pain in nulliparous women. These data do not support the routine use of misoprostol before IUD insertion in nulliparous women.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00886834.
LEVEL OF EVIDENCE: I
The intrauterine device (IUD) has efficacy comparable with sterilization and the highest degree of user continuation at 1 year of any reversible method.1 These attributes make the IUD an ideal contraceptive method for many women. Use of the IUD in the United States has risen from 2% in 2002 to 5.5% in 2006–2008.2 Despite this increase, the United States still lags behind the rest of the world in IUD use. One reason for this lag is that U.S. health care providers do not routinely recommend IUDs for nulliparous women. U.S. health care provider reluctance to recommend IUDs in nulliparous women exists despite the copper T380A IUD being Food and Drug Administration-approved for use in this group.3 In addition, the American Congress of Obstetricians and Gynecologists supports the use of both the copper T380A IUD and the levonorgestrel IUD in nulliparous women and considers it a first-line contraceptive option for nulliparous women including adolescents.4,5 Reasons for U.S. health care provider reluctance to offer nulliparous women intrauterine contraception are multifactorial and may include concerns about pain and infertility as well as confusion regarding labeling of the levonorgestrel IUD, which states “Mirena is recommended for women who have had at least one child.”3
Another component of health care provider resistance to nulliparous IUD insertion may be the smaller diameter, resistance of the nulliparous internal cervical os, or both which can lead to more difficult and more uncomfortable insertions. Misoprostol is commonly used to dilate the cervix for gynecologic procedures including first-trimester aspiration abortion, hysteroscopy, and endometrial biopsy.6–9 Because of misoprostol's known ability to cause cervical dilation in pregnancy, some family planning providers have begun using misoprostol to facilitate IUD insertion in nulliparous women with many health care providers now using misoprostol empirically.10
Data from studies of misoprostol use in the office setting are difficult to compare as a result of varying route and timing of misoprostol administration before obstetric and gynecologic procedures. Published randomized controlled trials assessing misoprostol before IUD insertion are a heterogeneous group and vary in parity of included participants, blinding, and prior use of an IUD. An unblinded study randomized nulliparous women to receive sublingual diclofenac or diclofenac and 400 μg misoprostol 1 hour before IUD insertion.11 The primary outcome was health care provider assessment of cervical resistance, which was judged to be less in the misoprostol group. Medication side effects were greater in the misoprostol group.11 Several blinded trials of misoprostol compared with placebo have failed to find a significant difference in patient perception of pain with insertion or health care provider-reported ease of insertion, whereas all studies have noted an increase in patient side effects associated with misoprostol.12–14 Evidence is growing that misoprostol before IUD insertion in nulliparous women actually increases discomfort associated with the procedure by adding prostaglandin side effects to the patient experience while not affecting the ease of insertion as experienced by the clinician.
Prior studies have administered misoprostol in the clinic and have favored short intervals between drug administration and IUD insertion. This may have decreased the ability of misoprostol to create its desired effect of cervical softening and dilation. Our study objective was to estimate the effects of self-administered misoprostol before IUD insertion in nulliparous women, permitting a greater time period of activity of the study drug. A randomized double-blind placebo-controlled trial was conducted in nulliparous women undergoing IUD insertion to determine whether the use of self-administered misoprostol decreases pain and eases insertion.
MATERIALS AND METHODS
The study was conducted at the outpatient obstetrics and gynecology clinic at the University of Utah in Salt Lake City, Utah, between January 2009 and November 2010. The trial was registered with ClinicalTrials.gov (NCT00886834) and approved by the University of Utah's institutional review board (00024403). A copy of the study protocol can be obtained from the University of Utah institutional review board. Informed consent was obtained and documented from all participants. Women who were seeking intrauterine contraception were offered participation in the trial if they were 18 years of age or older, had a negative pregnancy test, had no prior pregnancies beyond 13 6/7 weeks of gestation, and would be willing to follow-up in 1 month for an IUD string check. Women were excluded if they had an active cervical infection, pelvic inflammatory disease in the last 3 months, current pregnancy, prior pregnancy beyond 14 weeks of gestation, known uterine anomaly, uterine leiomyoma that distort the uterine cavity, copper allergy or Wilson's disease (for copper T380A), abnormal bleeding, a history of genital tract cancer, or used narcotics or benzodiazepines on the day of the procedure. Participants could choose between the two IUDs currently available in the United States (copper T380A or the levonorgestrel IUD).
Participants were randomized by computer-generated randomization by blocks of four to receive either 400 μg misoprostol or placebo. Both the drug and placebo were formulated by our study pharmacist for identical appearance, taste, and smell as well as absorption into a single troche acceptable for vaginal or buccal use. The University of Utah clinical research pharmacy generated the random allocation sequence and also dispensed the medication. Both participants and health care providers were blinded to allocation. Participants then were instructed to insert the troche either vaginally or buccally 3–4 hours before the IUD insertion appointment. They were given instructions regarding the greater likelihood of nausea or vomiting with buccal use and equal efficacy regardless of route as was done in a study using misoprostol for medical abortion.15 The dose, route, and timeframe for administration were determined based on prior family planning literature on first-trimester abortion.16–18 A Society of Family Planning Guideline for cervical dilation before first-trimester abortion thoroughly evaluated studies assessing misoprostol dose and timing.8 Recommendations based primarily on good and consistent scientific evidence from that review state: “When misoprostol is used before suction abortion, the optimal dose and timing are 400 μg vaginally 3–4 hours before the procedure.“ Buccal administration has similar pharmacokinetic and physiologic properties as vaginal administration.8 Recommendations based primarily on limited or inconsistent scientific evidence support vaginal or sublingual administration depending on patient preference with women finding both routes acceptable.8
In our study, only experienced health care providers, having placed 10 or more IUDs in the past year, participated in the study. Pre-IUD insertion and post-IUD insertion counseling was done per the clinic standard of care. The use of lidocaine at the tenaculum site, prophylactic analgesics (ibuprofen), or additional cervical analgesia (ie, paracervical or lower uterine segment block) was documented if used. Participants rated pain before, during, and after IUD insertion on a validated 100-mm visual analog scale (anchors: 0=none, 100 mm=worst imaginable). After insertion, the health care provider completed a brief questionnaire addressing ease of insertion based on a 100-mm visual analog scale (anchors: 0=extremely easy, 100 mm=impossible) and recorded any adjuvant measures used to facilitate IUD insertion (use of mechanical cervical dilation, ultrasonography, or any adjuvant analgesia).
Approximately 1 week after IUD insertion, participants were contacted by phone and questioned about use of pain medication, side effects experienced as well as maximum pain experienced during the first week after insertion. Patients were asked specifically to describe the discomfort with the IUD insertion and whether knowing now about the discomfort, they would repeat the procedure or recommend it to a friend. Participants then returned to the clinic in 1 month for a string check and a final questionnaire addressing patient satisfaction.
The sample size and power calculation were determined to detect a 15-mm difference in the primary outcome of participant perceived pain using the validated 100-mm visual analog scale.19 Prior use of this scale in family planning trials has considered a 15-point difference as significant.20 The standard deviation from prior studies was 23. For α=0.05, β=0.10, and 90% power, 50 participants were required in each group. Variables of interest were examined and tested for normality using the Shapiro-Wilks test. Because all of the variables of interest failed to meet the normality assumption, nonparametric methods, the Wilcoxon Mann–Whitney test, were used. Final analysis was by intention to treat. Data were analyzed using STATA 10.0 data analysis and statistical software. This study is part of a larger prospective meta-analysis registered with the Cochrane Collaboration that is powered to definitively assess whether misoprostol before IUD insertion in nulliparous women decreases the need for adjuvant measures to facilitate IUD insertion.4
Of the 108 participants enrolled in the study, 105 completed the study (Fig. 1). There were no significant differences between the two groups in terms of demographics. Nearly all participants (99 of 105 [94%]) chose to insert the pills vaginally, and the majority (78 of 105 [74%]) chose the levonorgestrel IUD (Table 1). There were no significant differences between the two groups regarding the need for cervical dilation, ultrasonography, paracervical block, or all of these (Table 2). There were five IUD insertion failures. Two insertion failures occurred in the misoprostol group. One participant's cervix could not be adequately dilated as a result of patient discomfort despite a paracervical block and the other participant had a cervical anomaly making insertion impossible. The three insertion failures in the placebo group were secondary to suspected bicornuate uterus, failure of cervical dilation as a result of patient pain, and patient discomfort during insertion as a result of a severely anteverted and anteflexed uterus. Three participants were excluded from final analysis in the placebo group, two as a result of premedication with unapproved medications (one with a benzodiazepine and one with a narcotic) and one for failure to return for insertion. There was no significant difference in the primary outcome of patient pain during IUD insertion (P=.74). Although not statistically significant, there is statistical evidence to suggest an increase in pain immediately after IUD insertion in those participants who received misoprostol (P=.07). Patient pain before IUD insertion was significantly higher in those participants randomized to misoprostol (misoprostol mean 17.1 mm [standard error 3.5], placebo mean 4.7 mm [standard error 2.0], P=.003) (Table 3). Health care provider–perceived ease of insertion was not significantly different between the two groups (misoprostol mean 25 mm [standard error 3.5], placebo mean 27.4 mm [standard error 3.5], P=.64). There were two expulsions in the misoprostol group and none in the placebo group; this difference was not significant (P=.50).
At approximately 1 week after the procedure more than half the women in both groups reported the pain with insertion as “severe” or “very severe” based on a 5-point Likert scale (Table 4). At the same time, when asked if knowing what they know now about the discomfort associated with IUD insertion how likely they were to have another IUD inserted or recommend the procedure to a friend, over three-fourths of women said they would (Tables 5 and 6). The experienced health care providers participating in the study were asked at the time of insertion if they believed the patient received study drug, placebo, or if they did not know. Health care providers were able to correctly identify participants who received the study drug less than half of the time (Table 7).
Our results demonstrate that self-administered misoprostol 3–4 hours before IUD insertion in nulliparous women does not reduce patient-perceived pain nor does it increase health care provider ease of insertion. This study adds to the accumulating evidence that misoprostol is not effective when attempting to ease IUD insertion from either the patient or health care provider perspective. Misoprostol has shown to be effective when used in the setting of medical abortion21 and early pregnancy failure22 but has not been effective before IUD insertion. Studies evaluating misoprostol before hysteroscopy have demonstrated mixed results; two recent meta-analyses have failed to show a convincing effect on cervical dilation.23,24 Although interesting, these results do not apply to the current study, because a significant proportion of participants were postmenopausal women. It is possible that the expected cervical dilation with the use of misoprostol in early pregnancy does not occur with the nonpregnant uterus as a result of changes in prostaglandin receptors in the cervix that occur with increased levels of progesterone. This has been shown in animal models25 and may explain the lack of effect with misoprostol before IUD placement.
The health care providers in our study were unable to correctly identify those participants who had received misoprostol before the procedure, which further supports our conclusion that misoprostol does not affect ease of insertion. In addition, prior studies have shown greater adverse gastrointestinal side effects with similar doses of misoprostol in this clinical situation.12–14 Additional evidence of detriment without support of gain suggests that despite hopes for benefit, use of misoprostol should be abandoned in this situation. It is reassuring, however, that despite the severe discomfort described by the patients in our study, the majority would repeat the procedure and recommend it to a friend.
Our study design did allow for self-administration (either buccally or vaginally) of the drug or placebo. The vast majority chose to insert the pills vaginally, a preference that has been demonstrated in previous studies.15 Because so few participants administered the medication buccally, we reanalyzed the data excluding patients who chose buccal administration (n=6). With these participants excluded, there were no significant differences in the results. Contrary to commercially formulated misoprostol, which, when inserted vaginally, often leaves behind fragments of tablets, no residual of our formulated study drug or placebo was seen vaginally in our study. This does raise several questions, the first of which is whether participants in our study actually took the pills. However, given our results, which showed a statistically significant increase in pain before IUD insertion in the misoprostol group, we can infer that participants did indeed take the pills as instructed. Second, because the formulation of misoprostol used in our study was completely absorbed by the time of IUD insertion, this raises the question of a possible discrepancy in pharmacokinetics between commercially formulated misoprostol and the misoprostol used in our study. It could be inferred that because our study misoprostol appeared to dissolve more readily that peak plasma time after vaginal insertion might be sooner than the 3–4 hours established for commercially formulated misoprostol. To answer this question, we will be conducting a study comparing peak plasma times after vaginal insertion of our study misoprostol compared with commercially available misoprostol.
Although this study is not adequately powered to detect a difference in expulsion rates between the two groups, we did observe two IUD expulsions during the follow-up period in the misoprostol group and none in the placebo group. Increased uterine tone could theoretically explain this occurrence, but given the negative results from prior studies, there is no need to pursue this line of investigation further.
Data from this project will be contributed to a prospective meta-analysis powered to assess the difference between the inability to place the device as well as the need for adjuvant measures (use of cervical anesthesia, cervical dilation, or use of ultrasonographic guidance) to achieve insertion between women receiving misoprostol and placebo.4 None of the included studies are independently powered to assess this outcome. Currently available evidence shows a lack of benefit with misoprostol before IUD insertion and increased adverse effects. The use of misoprostol before IUD insertion did not demonstrate a positive treatment effect and alternative methods to decrease pain during the procedure and increase ease of insertion should be pursued.
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© 2012 The American College of Obstetricians and Gynecologists
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