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Misoprostol for intrauterine device insertion in nulliparous women: a randomized controlled trial Eve Espey, MD, MPH; Rameet H. Singh, MD, MPH; Lawrence Leeman, MD, MPH; Tony Ogburn, MD; Kylie Fowler, MD; Heather Greene, MD OBJECTIVE: To examine the effects of preprocedure misoprostol on

RESULTS: Of 85 women enrolled, 3 were ineligible; 42 were ran-

intrauterine device (IUD) placement in nulliparous women.

domized to misoprostol and 40 to placebo. There were no differences between groups in worst insertion pain, (5.8  2.0 vs 5.9  2.0, P ¼ .94), provider ease of insertion (2.2  2.2 vs 2.5  2.2; P ¼ .54) or adjunctive measures (14% vs 25%; P ¼ .27). The groups were willing to tolerate the same mean pain (4.9  2.5 vs 5.7  2.4, P ¼ .18) to avoid waiting for medication. The majority of women (85%) preferred to wait for an effective medication.

STUDY DESIGN: In this randomized controlled double-blind trial at the University of New Mexico reproductive health clinic, nulliparous women requesting an IUD were randomized to 400 mcg of buccal misoprostol or placebo 2-8 hours before insertion. Primary outcomes included pain on a 10-cm visual analog scale and women’s perception of the value of delaying insertion for an effective medication. Provider ease of insertion and need for adjunctive insertion measures were also assessed, on a visual analog scale. Participants indicated maximum pain after IUD insertion, pain level they would tolerate to avoid delay in IUD insertion, and preference for IUD insertion without delay if an effective medication was available.

CONCLUSION: Misoprostol for nulliparous women did not decrease pain or improve the ease of insertion of an IUD. Most women were willing to wait for a medication that decreases pain, indicating a need to pursue alternatives for pain control with IUD insertion.

Key words: cervical preparation, ease of insertion, nulliparous women, pain with insertion

Cite this article as: Espey E, Singh RH, Leeman L, et al. Misoprostol for intrauterine device insertion in nulliparous women: a randomized controlled trial. Am J Obstet Gynecol 2014;210:208.e1-5.

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ain with intrauterine device (IUD) insertion is a potential deterrent for nulliparous women considering an IUD and their health care providers.1 Many nulliparous women are adolescents or young women at high risk for unintended pregnancy who could benefit from the use of highly effective longacting reversible contraceptive methods like the IUD. Although the majority of From the Departments of Obstetrics and Gynecology (Drs Espey, Singh, Ogburn, and Fowler) and Family and Community Medicine (Drs Leeman and Greene), University of New Mexico School of Medicine, Albuquerque, NM. Received Aug. 4, 2013; revised Sept. 27, 2013; accepted Nov. 6, 2013. The study received funding from the Department of Obstetrics and Gynecology, University of New Mexico School of Medicine. Clinical trial registration number: NCT01001897. The authors report no conflict of interest. Reprints are not available from the authors. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.11.018

nulliparous women are good candidates for the IUD, many providers, including family medicine physicians, obstetrician gynecologists, and advanced practice clinicians remain reluctant to consider IUDs for adolescents or nulliparous women.2,3 Identifying an effective approach to reducing pain with IUD insertion remains elusive: trials of prophylactic ibuprofen and paracervical block have not demonstrated pain reduction.4,5 The perception that IUD insertion is difficult and causes significant pain may contribute to providers’ hesitation to offer the method or to use measures like misoprostol that have unproven success.6 The IUD has a 0.2-0.3% failure rate with minimal opportunity for user error and high rates of user satisfaction.7 Although use of IUDs has increased among all women in the United States to 7.7% in 2009, only 2.1% of nulliparous women use the IUD.8 The Institute of Medicine has prioritized increasing LARC use among young women to decrease unintended pregnancies.9 The

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US Medical Eligibility Criteria and the American College of Obstetricians and Gynecologists support use of both the copper and levonorgestrel IUD in nulliparous women, including adolescents.10,11 The Contraceptive CHOICE project provided contraceptives at no cost to almost 10,000 women. In total, 41.2% of women in the CHOICE project who chose a LARC method were nulliparous.12 Misoprostol, a prostaglandin E1 analogue used in gynecology for cervical ripening, has demonstrated effectiveness in decreasing pain and complications with both surgical abortion and hysteroscopy.13,14 Several studies have examined the use of misoprostol as a cervical priming agent before IUD insertion in nulliparous women with mixed results.15-18 The use of misoprostol before IUD insertion requires a time delay, which may be considered a deterrent to the nulliparous woman considering an IUD. The aim of our study is to determine whether prophylactic misoprostol use reduces pain or improves ease of

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FIGURE

Flow diagram

The diagram demonstrates numbers of participants who were randomly assigned, received the intended treatment and were analyzed. Espey. Misoprostol for IUD insertion in nulliparous women. Am J Obstet Gynecol 2014.

insertion with IUD placement, and to determine the opportunity cost of the time delay required to administer misoprostol before IUD insertion. We sought to determine women’s perceptions of whether the possible benefit of decreased discomfort or difficulty of insertion was worth the 2- to 3-hour delay before IUD insertion and whether higher pain was a reasonable price to pay for immediate insertion.

M ATERIALS

AND

M ETHODS

This double-blind, randomized placebocontrolled parallel-group trial was conducted at the University of New Mexico (UNM) reproductive health clinic in Albuquerque, New Mexico, from Jan. 2010 to Jan. 2013 and was approved by the UNM Human Research Protections Office. This study will contribute data to a prospective metaanalysis coordinated by the University of Utah on the need for adjunctive measures such as mechanical cervical dilation during IUD insertion in nulliparous women. Nulliparous women desiring a levonorgestrel intrauterine system or copper T-380A IUD for contraception were

recruited for the study. Inclusion criteria included English speaking women aged 18 and over, or aged 14-17 with parental consent. Women with history of a pregnancy lasting beyond 19 6/7 weeks, any pregnancy within the last 4 weeks, active genital infection or cervicitis, undiagnosed abnormal uterine bleeding, fibroids distorting the uterine cavity, history of cervical or uterine cancer, uterine anomaly, pelvic inflammatory disease within the last 3 months, and ibuprofen or copper allergy, were excluded. Pharmacists at the University of Utah Health Sciences Center clinical research pharmacy not directly involved in the study performed randomization and preparation of the study and placebo medications. Randomization was based on computer generated 8-block randomization sequences. The drug and placebo tablets were identical in appearance, taste and smell and packaged according to the randomization list in matching bottles labeled with consecutive numbers. These were sent to UNM and the bottles were pulled in sequential order. Participants were randomly allocated in a 1:1 ratio either to treatment with 400 mcg of misoprostol

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or placebo. The medication was placed buccally for 30 minutes and subjects were instructed to swallow any remaining medication. Buccal administration was chosen for its excellent bioavailability and ease of use.19 Participants and investigators were blinded to the assignment to treatment groups. Participants received standard counseling for IUD insertion and signed informed consent for the procedure and for study participation. After enrollment, participants received a $20 gift card to compensate them for their time. Participants underwent IUD placement 2-8 hours after receiving the study medication. This timeframe allowed women the option of waiting in clinic or returning later the same day. Participants completed a questionnaire before IUD insertion including demographic characteristics, anticipated pain with the procedure, use of pain medication, and side effects from the study medication. Premedication with nonsteroidal antiinflammatory agents is not typically offered in our practice and was not offered to study participants. All participants were asked if they had selfmedicated before the procedure. The IUD was placed using standard technique by 1 of 5 attending physicians skilled in IUD insertion, at the UNM’s reproductive health clinic. If difficulty was encountered during insertion, the attending physicians had the option of using adjunctive measures including an os finder, a soft endometrial biopsy device, Denniston dilators, ultrasound assistance, or additional analgesia. Patients reported pain on a 10-cm visual analog scale (VAS) with anchors at 0 ¼ none and 10 ¼ worst imaginable pain. Pain was evaluated at baseline when legs were positioned in stirrups, immediately after IUD insertion (after instruments were removed from the vagina), and before discharge from the clinic. Participants were provided the VAS and marked their pain on the 10 cm line accordingly. Before discharge, the research assistant also asked the participant her preference for having the IUD placed without a delay for a medication to decrease insertion pain (4-point Likert scale with

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General Gynecology

anchors: 1 ¼ strongly prefer IUD placement without the wait, 4 ¼ strongly prefer to wait for IUD placement for medicine effect) and how much pain she was willing to tolerate to have immediate IUD placement without waiting for the medicine on a 10-cm VAS (anchors 0 ¼ no pain, 10 ¼ worst pain imaginable). We asked the last 2 questions after IUD insertion to allow for the possibility that the degree of insertion pain could influence the preference for a delay to await the effect of medication. If the preprocedure misoprostol reduced insertion pain, women’s preferences for delay might differ between the misoprostol and placebo groups. Providers completed a questionnaire including perceived ease of IUD insertion on a 10-cm VAS (0 ¼ easy and 10 ¼ extremely difficult), and need for adjunctive measures. Participants were scheduled to return to clinic in 1-2 weeks for a standard IUD check visit at which time women reported pain since IUD insertion, complications, and satisfaction. Study investigators contacted participants unable to keep their appointment within 4 weeks of insertion and conducted a telephone interview to collect the same information. The sample size of 80 women was determined based on our participation in the prospective metaanalysis. Before initiation of the study, we determined that this sample size, equally distributed between the misoprostol and placebo groups, would detect a 0.8 cm  1.25 difference between mean maximum pain with IUD insertion on the VAS with a power of 80% and a ¼ 0.05 (2-tailed). Evidence from the family planning literature suggests a 1.5 cm difference is clinically meaningful.20 A sample size of 80 would also allow a 29% detectable difference between groups when 49% in 1 group prefer to wait compared with 20% in the other, with 80% power and a ¼ 0.05 (2-tailed). To evaluate differences between groups, Fisher exact test was used for categorical and the t test was used for continuous variables. Statistical significance was set at P  .05. We analyzed the data using SAS statistical software (version 9.3; SAS Institute Inc., Cary, NC).

TABLE 1

Demographic characteristics Characteristics

Misoprostol n [ 42

Placebo n[ 40

P value

Age (mean  SD)

24.1  4.3

24.1  4.6

.99

Race

.75

White

25 (59)

22 (50)

Hispanic or Latina

12 (29)

14 (35)

5 (12)

6 (15)

Other Marital status

.40

Single

30 (71)

33 (85)

Married/Cohabitating

10 (24)

5 (13)

1 (5)

1 (2)

1 (1)

5 (12)

Some college

17 (41)

15 (38)

Graduated from college

17 (41)

15 (38)

7 (17)

5 (12)

Prior miscarriage/abortion

9 (21)

4 (10)

.16

History of STI

8 (19)

3 (7)

.20

36 (86)

36 (90)

.74

6 (14)

4 (10)

Yes

26 (62)

16 (40)

No

16 (38)

24 (60)

Other Level of education High school/GED

Completed graduate school

.42

Type of IUD Levonorgestrel IUS Copper T380A Medication before IUD insertion .08

All cells n (%) unless otherwise specified. GED, general equivalency degree; IUD, intrauterine device; IUS, intrauterine system; STI, sexually transmitted infections. Espey. Misoprostol for IUD insertion in nulliparous women. Am J Obstet Gynecol 2014.

R ESULTS A total of 85 women were enrolled; 2 were ineligible (Figure). Of the 83 women randomized, 1 was ineligible, leaving 42 women randomized to misoprostol and 40 to placebo. Followup was completed for 40 women in each group. Two women were lost to follow-up in the misoprostol group. There were no differences in baseline characteristics between the 2 groups (Table 1). Anticipated pain (P ¼ .11) and pain before IUD insertion (P ¼ .31) did not differ between groups. There was no difference in use of pain medication before IUD insertion in the 2 groups (P ¼ .08). An oral opioid was used by

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10% and either ibuprofen or acetaminophen was used by 90% of women who self-medicated before the IUD insertion appointment; type of medication did not differ between the 2 groups (P ¼ .15). The highest level of pain immediately after IUD insertion was similar between the misoprostol and placebo groups (5.8  2.0 vs 5.9  2.0, P ¼ .94). There were no differences between groups with respect to symptoms of nausea, vomiting, or diarrhea (Table 2). The amount of pain women were willing to tolerate to avoid waiting to have the IUD inserted did not differ between the groups (P ¼ .18). Most women in both groups (85%) reported that, if available, they would

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TABLE 2

Nulliparous women’s pain experience, misoprostol group vs placebo group, with IUD insertion Mean ± SD

Misoprostol n [ 42

Placebo n [ 40

P value

Anticipated pain with IUD insertion

5.9  1.7

5.3  1.7

.11

Pain before IUD insertion after miso/placebo

0.5  1.2

0.8  1.7

.31

Nausea, n (%)

7 (17)

12 (30)

.19

Vomiting

0 (0)

1 (3)

.50

Diarrhea

1 (2)

1 (3)

e

Fever

0

0

Highest level of pain, immediately after IUD insertion

5.8  2.0

5.9  2.0

.94

Pain before discharge from clinic

3.2  2.2

3.8  2.7

.29

5 (12)

7 (17)

.54

37 (88)

33 (83)

Given experience with IUD insertion Somewhat or strongly prefer IUD placed without wait Somewhat or strongly prefer to wait for IUD placement for medicine effect

4.9  2.5

Amount of pain willing to take to avoid wait

5.7  2.4

.18

Espey. Misoprostol for IUD insertion in nulliparous women. Am J Obstet Gynecol 2014.

each group found it easy to place the IUD in nulliparous women with a mean ease of insertion score of 2.2  2.2 in the misoprostol group and 2.5  2.2 in the placebo group (P ¼ .54) based on the VAS. A total of 3 IUDs were expelled, 1 in the misoprostol group and 2 in the placebo group. One IUD in the misoprostol group was removed for bleeding and cramping 11 days after insertion.

TABLE 3

IUD insertion outcomes in nulliparous women, misoprostol group vs placebo group Variable

Misoprostol n [ 42 n (%)

Placebo n [ 40 n (%)

P value

Successful IUD insertion

42 (100)

40 (100)



6 (14)

10 (25)

.27

38 (90)

38 (95)

.68

Need for adjunctive measures (dilation/ultrasound) IUD continuation IUD expulsion/removal Use of medication after IUD insertion

2 (5)

a

27 (68)

a

IUD, intrauterine device. a

n ¼ 40 (n ¼ 2 lost to follow-up).

Espey. Misoprostol for IUD insertion in nulliparous women. Am J Obstet Gynecol 2014.

Three women from the misoprostol group and two women from the control group had an unscheduled visit related to the IUD. The majority of women in each group used pain medication after insertion (68% misoprostol group vs 65% placebo group, P > .99). Women described the experience of pain with IUD insertion as moderate; 50% in the misoprostol group vs 40% in the placebo group, (P ¼ .6), but 65% of women in each group reported that the experience of pain would not influence their choice of an IUD in the future (P > .99). Overall, women (98% misoprostol vs 88% placebo, P ¼ .12) were satisfied or very satisfied at follow-up with using the IUD.

C OMMENT

IUD, intrauterine device.

prefer to wait for a medicine to take effect to reduce pain with IUD insertion. All IUDs were successfully placed in each group (Table 3). Eighteen women required adjunctive measures to accomplish IUD insertion (6 in the misoprostol and 10 in the placebo group, P ¼ .27). Providers did not indicate any difference in ease of IUD insertion between groups (P ¼ .54). Providers in

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2 (5)

> .99

26 (65)

> .99

The main findings of our study were no differences in pain during IUD insertion between women who received preprocedure misoprostol or placebo and no differences in provider perceptions of ease of insertion or need for use of adjunctive measures to accomplish IUD insertion. We found no differences in side effects, including pain, fever, nausea, diarrhea, or vomiting between women who received misoprostol vs placebo. The study confirms that IUD insertion is a painful procedure, and most nulliparous women report they would prefer to wait for a medication that reduced the pain of IUD insertion. We have confirmed the findings of 4 earlier randomized controlled trials demonstrating considerable pain with IUD insertion (9-12) and no reduction in insertion pain with 400 mcg of misoprostol. In these studies the mean VAS scores were 5.5 control, 6.5 misoprostol,15 5.4 control, 5.9 misoprostol,16 5.7 control, 5.8 misoprostol,17 and 6.5 control, 7.0 misoprostol.18 These trials also showed no benefit in patient reported pain or provider perceived ease of insertion; however, they reported an increase in side effects in the treatment group. Treatment protocols in these studies varied in route of administration (vaginally or buccally) and timing of administration (90 minutes to 4 hours before insertion).

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In a Swedish study of 80 nulliparous women randomized to misoprostol and diclofenac vs diclofenac alone an hour before IUD insertion, there was no difference in patient-reported pain scores or side effects; a small statistically significant increase in provider ease of insertion was reported in the misoprostol group.18 Only 1 failed insertion occurred in the study, suggesting that ease of insertion does not affect the ability to insert. Despite lack of evidence supporting its use, in a survey of health care providers who provided IUDs to nulliparous women, 49% of respondents reported sometimes or always using misoprostol for cervical ripening before insertion.21 Of those who used it, 54% reported misoprostol use facilitated IUD insertion “a lot.” Our findings suggest that routine use of misoprostol before IUD insertion in nulliparous women is a potential barrier to IUD use given the wait required for use of misoprostol and lack of any benefit. Because complications with IUD insertion are rare, even in nulliparous women, interventions to facilitate ease of insertion should be balanced against potential barriers created by the intervention. Requiring a woman to be on her menses or requiring 2 visits for IUD insertion constitute barriers to insertion. A recent study demonstrated that 2-visit insertion protocols instituted because of Medicaid requirements inhibit IUD placement: of 708 women who requested IUD insertion at the initial visit, only 54% had the IUD inserted.22 At 1 institution, among postpartum women who stated a preference for an IUD at hospital discharge, only 65% returned to have one placed.23 Perhaps the largest barrier to IUD insertion in nulliparous women, however, is providers’ attitudes. A 2012 study of 635 office based physicians and 1323 Title X physicians and advanced practice clinicians indicated that over 60% rarely provided IUDs to nulliparous women, partly based on misconceptions about the safety of IUDs.3 Our study is limited by the fact that all IUDs were inserted by experienced family planning faculty members who

routinely place IUDs in nulliparous women. It is possible that misoprostol could have a beneficial effect when used by patients whose providers have less experience. Our study examined routine use of misoprostol in nulliparous women. It is possible that selective use in women experiencing a difficult insertion may prove to be of benefit. Our study adds to the evidence that routine use of misoprostol in nulliparous women does not improve the ability to insert an IUD or reduce pain with insertion. It does point out that nulliparous women experience considerable pain with IUD insertion, evidenced by a willingness to tolerate some inconvenience for an intervention that would reduce pain. These findings suggest the advisability of continuing efforts to develop novel approaches to reduce pain with IUD insertion. -

REFERENCES 1. Allen R, Bartz D, Grimes D, Hubacher D, O’Brien P. Interventions for pain with intrauterine device insertion. In: The Cochrane library [CDROM]. Chichester, UK: John Wiley and Sons, Ltd. 1996. CD-ROMs: 4 3/4 in. Article no. CD007373. 2. Harper CC, Henderson JT, Raine TR, et al. Evidence-based IUD practice: family physicians and obstetrician-gynecologists. Fam Med 2012; 44:637-45. 3. Tyler CP, Whiteman MK, Zapata LB, Curtis KM, Hillis SD, Marchbanks PA. Health care provider attitudes and practices related to intrauterine devices for nulliparous women. Obstet Gynecol 2012;119:762-71. 4. Mody SK, Kiley J, Rademaker A, Gawron L, Stika C, Hammond C. Pain control for intrauterine device insertion: a randomized trial of 1% lidocaine paracervical block. Contraception 2012;86:704-9. 5. Hubacher D, Reyes V, Lillo S, Zepeda, Chen PL, Croxatto H. Pain from copper intrauterine device insertion: randomized trial of prophylactic ibuprofen. Am J Obstet Gynecol 2006;195:1272-7. 6. Allen RH, Goldberg AB, Grimes DA. Expanding access to intrauterine contraception. Am J Obstet Gynecol 2009;201:456.e1-5. 7. Trussell J. Contraceptive failure in the United States. Contraception 2011;83:397-404. 8. Finer LB, Jerman J, Kavanaugh ML. Changes in use of long-acting contraceptive methods in the United States, 2007-2009. Fertil Steril 2012;98:893-7.

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www.AJOG.org 9. Committee on Comparative Effectiveness Research Prioritization, Institute of Medicine. Initial National Priorities for Comparative Effectiveness Research. Washington, DC: The National Academies Press; 2009:252. 10. US medical eligibility criteria for contraceptive use, 2010. MMWR Recomm Rep 2010;18. 59(RR-4):1-86. 11. Committee opinion no. 539: adolescents and long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol 2012;120:983-8. 12. Winner B, Peipert JF, Zhao Q, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366:1998-2007. 13. Allen RH, Goldberg AB; Board of Society of Family Planning. Cervical dilation before firsttrimester surgical abortion (< 14 weeks’ gestation). SFP Guideline 20071. Contraception 2007;76:139-56. 14. Preutthipan S, Herabutya Y. Vaginal misoprostol for cervical priming before operative hysteroscopy: a randomized controlled trial. Obstet Gynecol 2000;96:890-4. 15. Edelman AB, Schaefer E, Olson A, et al. Effects of prophylactic misoprostol administration prior to intrauterine device insertion in nulliparous women. Contraception 2011;84: 234-9. 16. Dijkhuizen K, Dekkers OM, Holleboom CA, et al. Vaginal misoprostol prior to insertion of an intrauterine device: an RCT. Hum Reprod 2011;26:323-9. 17. Swenson C, Turok DK, Ward K, Jacobson JC, Dermish A. Self-administered misoprostol or placebo before intrauterine device insertion in nulliparous women: a randomized controlled trial. Obstet Gynecol 2012;120(Pt 1):341-7. 18. Saav I, Aronsson A, Marions L, Stephansson O, Gemzell-Danielsson K. Cervical priming with sublingual misoprostol prior to insertion of an intrauterine device in nulliparous women: a randomized controlled trial. Hum Reprod 2007;22:2647-52. 19. Choksuchat C. Clinical use of misoprostol in nonpregnant women: review article. J Minim Invasive Gynecol 2010;17:449-55. 20. Edelman AB, Nichols MD, Leclair C, Astley S, Shy K, Jensen JT. Intrauterine lidocaine infusion for pain management in first-trimester abortions. Obstet Gynecol 2004;103:1267-72. 21. Ward K, Jacobson JC, Turok DK, Murphy PA. A survey of provider experience with misoprostol to facilitate intrauterine device insertion in nulliparous women. Contraception 2011;84:594-9. 22. Bergin A, Tristan S, Terplan M, Gilliam ML, Whitaker AK. A missed opportunity for care: two-visit IUD insertion protocols inhibit placement. Contraception 2012;86:694-7. 23. Ogburn JA, Espey E, Stonehocker J. Barriers to intrauterine device insertion in postpartum women. Contraception 2005;72:426-9.

Misoprostol for intrauterine device insertion in nulliparous women: a randomized controlled trial.

To examine the effects of preprocedure misoprostol on intrauterine device (IUD) placement in nulliparous women...
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