Misoprostol Prior to IUD Insertion in Nulliparous Women: Where’s the Benefit?
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH
Synopsis: In a randomized study of nulliparous women who presented for insertion of a copper IUD, the ease of insertion was increased, and subjective pain decreased in those who received vaginal misoprostol prior to the procedure. However, misoprostol did not decrease failed insertions and was associated with a trend toward more expulsions.
Source: Scavuzzi A, et al. Misoprostol prior to inserting an intrauterine device in nulligravidas: A randomized clinical trial. Hum Reprod 2013;28:2118-2125.
Several groups have evaluated whether the routine use of misoprostol could improve the intrauterine device (IUD) placement experience for women. While well-intended, these efforts have failed to demonstrate that the approach results in an increase in successful insertion attempts or that benefit surpassed potential harm. Scavuzzi et al performed a randomized, double-blind, clinical trial at a single hospital-based clinic in Brazil. They recruited healthy nulligravid women and randomized them to receive 400 mg of misoprostol or an identical placebo tablet vaginally 4 hours prior to placement of a CuT380 IUD. The study drug was placed in the posterior fornix of the vagina by the principal investigator. The primary outcome was the subjective difficulty (as reported by the investigator) in inserting the IUD. Secondary endpoints included the frequency of women with cervical dilation ≤ 4 mm (measured by ease of inserting a #4 Hegar dilator), pain at insertion (as judged subjectively by the woman and the investigator using a visual analog scale), and the woman’s subjective evaluation of the procedure (classified as not disagreeable, slightly disagreeable, disagreeable, or very disagreeable). The investigators also evaluated the frequency of pre-procedure side effects such as nausea and cramping.
A total of 190 women were randomized (95 in each group). Fewer placements were judged to be "difficult/very difficult" in the misoprostol group compared to the placebo group (relative risk [RR], 0.49; 95% confidence interval [CI], 0.33-0.72), and active drug was also associated with a lower risk of dilatation < 4 mm (RR, 0.48; CI, 0.33-0.70), a reduction in moderate-to-severe pain at IUD insertion (RR, 0.56; CI, 0.41-0.76), and a lesser likelihood of experiencing a "disagreeable or very disagreeable sensation" (RR, 0.49; CI, 0.35-0.68). These beneficial findings were offset by an increased risk of pre-procedure cramps in the misoprostol group (RR, 1.40; CI, 1.05-1.86), but no significant increase in nausea, vomiting, or diarrhea. Notably, treatment did not influence the overall risk of failed IUD placement (4/86 [4.1%] misoprostol, 3/93 [3.2%] in the placebo group), but was associated with a trend toward increased expulsion within 30 days (3/82 [3.7%] misoprostol, 1/90 [1.1%] placebo). In the published structured abstract for this paper, under the section "limitations, reasons for caution," the authors state that "the positive results do not imply that use of misoprostol is imperative prior to IUD insertion in nulligravidas and IUD insertion should not be canceled when the medication is unavailable," and then add under the header "wider implications of the findings" that "in view of its effect in promoting cervical dilatation, misoprostol may be used prior to IUD insertion both in nulligravidas and in any women with cervical stenosis irrespective of parity."
The use of misoprostol in gynecology is quickly becoming like the use of bacon in cuisine. Since it is tasty and good in some dishes, many chefs (and investigators) want to wrap it around everything. While this might appeal to teenage boys with the appetite and metabolism to withstand the dietary assault, common sense would suggest that the strategy is gratuitous and potentially harmful. So is misoprostol prior to IUD placement something special, or just ham wrapped in bacon?
First, three prior randomized studies have failed to support a direct benefit to the routine use of misoprostol prior to IUD insertion.1-3 The bottom line from all of these papers is that misoprostol does soften the cervix, but that this does not reduce the failed placement rate. The cervical softening also comes at the expense of significant side effects of cramping, bleeding, and nausea prior to the procedure. Some studies have also shown that procedure-related pain is actually increased rather than decreased. With no real benefit and potential harm, the intervention has lost favor among family planning experts.
But if the evidence is clear, why does the Scavuzzi paper deserve scrutiny? These investigators used vaginal administration of misoprostol to reduce troublesome gastrointestinal (GI) side effects. While the overall effect of no reduction in failed IUD placement was no different than with buccal misoprostol, it is not surprising that this approach worked to reduce GI side effects. The same strategy was commonly used for medical abortion (MAB) in the United States prior to 2005, when several cases of death associated with Clostridium sordellii were described in otherwise healthy women treated with oral mifepristone followed by vaginal misoprostol.4 Although it is not clear whether the vaginal route of administration of misoprostol was a causal factor in these rare infections, the absence of any reports in Europe (where MAB was common and vaginal misoprostol was not used) led to shift in practice patterns away from vaginal administration in the United States. Since the change to buccal misoprostol for MAB, no further cases of C. sordellii have been reported. Although the risk of serious infection following IUD placement is not likely to be influenced by misoprostol, there are other considerations. Vaginal administration produces a lower and delayed peak drug level, but a longer overall duration of effect. For this reason, the investigators needed to place misoprostol in the vagina 4 hours prior to IUD insertion. Presumably, women could self-administer the drug prior to the clinic visit to avoid the unnecessary exam and extra clinic time, but we have no evidence that self-administration would be associated with the same clinical benefit, or that this self-administration would be acceptable. Of greater concern is the trend toward more expulsions seen with misoprostol use. Although the number of events was small in both groups, almost 4% of placements following misoprostol resulted in expulsion within 30 days compared with only 1% in the placebo group. Given that the intervention did not reduce the proportion of failed IUD placements (about 5% in the misoprostol group vs 3% in the placebo group), this tendency toward harm is deeply concerning.
The study by Scavuzzi et al is a good reminder of why it is important to read more than the abstract of any manuscript prior to altering clinical practice. Although the authors state that the data were analyzed according to intention-to-treat rules, outcomes were not presented for nine women randomized to misoprostol (including one woman who dropped out after receiving misoprostol and did not receive an IUD) and for two subjects randomized to placebo. Did the women who dropped out of the study experience severe cramps that led to their decision not to proceed with placement? If so, these women left the clinic with a less-effective method of contraception that placed them at higher risk of unintended pregnancy. While GI side effects were no different in the treatment groups, pre-procedure cramping pain occurred more commonly in the misoprostol-treated subjects. Finally, the fact that the scale used to report ease of insertion was dichotomized as "easy" or "difficult/very difficult" rather than continuous or ordinal suggests the possibility of post-hoc data manipulation to obtain statistical significance.
Most IUD placements are straightforward and uneventful, even in nulliparous women. That said, the procedure can be uncomfortable, and we need to be both honest and supportive as we counsel our patients. Gentle technique, reassuring words, and the judicious use of paracervical block when cervical dilation is needed can help considerably. Although further research is needed to identify strategies to improve the insertion experience, the current evidence does not support the routine use of misoprostol.
References
- Heikinheimo O, et al. Double-blind, randomized, placebo-controlled study on the effect of misoprostol on ease of consecutive insertion of the levonorgestrel-releasing intrauterine system. Contraception 2010;81:481-486.
- Saav I, et al. Cervical priming with sublingual misoprostol prior to insertion of an intrauterine device in nulliparous women: A randomized controlled trial. Hum Reprod 2007;22:2647-2652.
- Edelman AB, et al. Effects of prophylactic misoprostol administration prior to intrauterine device insertion in nulliparous women. Contraception 2011;84:234-239.
- Fischer M, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005;353:2352-2360.
