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Naproxen reduces bleeding after placement of LNG-IUS

Clinical Question:
Does oral naproxen or transdermal estradiol reduce the number of bleeding and spotting days versus placebo in the first 12 weeks after insertion of the levonorgestrel intrauterine system?

Bottom Line:
After insertion of the levonorgestrel intrauterine system (LNG-IUS), bleeding and spotting were less frequent among women taking naproxen than among those taking placebo. Transdermal estradiol increased the risk of bleeding versus placebo. (LOE = 1b-)

Madden T, Proehl S, Allsworth JE, Secura GM, Peipert JF. Naproxen or estradiol for bleeding and spotting with levonorgestrel intrauterine system: a randomized controlled trial. Am J Obstet Gynecol 2012;206(2):129.e1-8.  [PMID:22055339]

Study Design:
Randomized controlled trial (double-blinded)

Industry + govt


Outpatient (primary care)

This study was a randomized controlled trial including 129 women embedded in a cohort of women beginning the LNG-IUS (Mirena). The purpose of the study was to determine whether oral naproxen 500 mg twice daily or transdermal estradiol 0.1 mg weekly would result in fewer bleeding and spotting days during the first 12 weeks after insertion. Bleeding was defined as requiring more than 1 pad or tampon in 24 hours. Spotting was defined as visible blood requiring not more than 1 pad or tampon. The study was double blind for naproxen versus placebo, and open label for transdermal estradiol for lack of a suitable placebo patch. Naproxen was used for the first 5 days of each 4-week period. The estradiol patch was used continuously for 12 weeks, changed weekly. To perform an intention-to-treat analysis of bleeding and spotting days, missing bleeding and spotting data was imputed by estimating the missing values. A total of 18% of women were lost to follow up: 14% in the naproxen group, 14% in the placebo group, and 22% in the estradiol group. It is not clear to what extent imputing these data with estimates jeopardizes the validity of the study. Bleeding days were skewed toward the earlier weeks of the study period requiring use of nonparametric statistical analysis. The authors compared distribution of quartiles of bleeding days. The lowest quartile of bleeding/spotting days (2-21 days) was more frequent among women in the naproxen versus placebo groups (43% vs 16%; P = .03). In multivariate analysis, the reduction in bleeding/spotting days with naproxen was approximately 10% as compared with placebo. On the other hand, women in the estradiol group were more likely than those in the placebo group to be in the highest quartile of bleeding/spotting days (54-84 days; 41% vs 19%; P = .02).


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