Treatment of bleeding irregularities in women with copper-containing IUDs: a systematic review

Contraception xx (2012) xxx – xxx

Review article

Treatment of bleeding irregularities in women with copper-containing IUDs: a systematic review☆ Emily M. Godfrey a, b,⁎, Suzanne G. Folger a , Gary Jeng a , Denise J. Jamieson a , Kathryn M. Curtis a a Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA Department of Obstetrics and Gynecology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA Received 3 July 2012; revised 31 August 2012; accepted 6 September 2012

b

Abstract Background: Bleeding irregularities, such as intermenstrual spotting or heavy or prolonged menstrual bleeding, are common among coppercontaining intrauterine device (Cu-IUD) users and are one of the leading reasons for method discontinuation. This review evaluates the evidence for effective therapeutic and preventive treatments for bleeding irregularities during Cu-IUD use. Study Design: We searched the PubMed database for peer-reviewed articles that were published in any language from inception of the database through March 2012 and were relevant to treatments for irregular bleeding during Cu-IUD use. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. Results: From 1470 articles, we identified 17 articles that met our inclusion criteria. Evidence from two studies of poor quality demonstrated that antifibrinolytic agents or nonsteroidal anti-inflammatory drugs (NSAIDs) have been used for intermenstrual bleeding or spotting among a small number of Cu-IUD users with mixed results. Evidence from 10 studies of fair to poor quality suggested that some NSAIDs may significantly reduce menstrual blood loss or bleeding duration among Cu-IUD users with heavy or prolonged menstrual bleeding. Antifibrinolytic drugs or antidiuretics may also help reduce blood loss. High-dose aspirin was shown to increase blood loss among those with baseline menorrhagia. Evidence from five studies of fair to poor quality suggested that bleeding irregularities among new Cu-IUD users may be prevented with NSAIDs, although one large study of good quality suggested that prophylactic treatment with ibuprofen does not affect continuation of Cu-IUD use. Evidence from two studies of fair to poor quality suggested that antifibrinolytic agents might be helpful in preventing heavy or prolonged menstrual bleeding among new Cu-IUD users. Conclusions: Limited evidence suggests that NSAIDs may be effective treatments for bleeding irregularities associated with Cu-IUD use; antifibrinolytic agents and antidiuretics have also been studied as possible treatments in a small number of subjects, but their safety has not been well documented. NSAIDs and antifibrinolytics may also prevent bleeding irregularities among new CU-IUD users. Preventive NSAID use, however, does not impact Cu-IUD continuation. © 2012 Elsevier Inc. All rights reserved. Keywords: Contraception; Intrauterine device; Intrauterine contraception; Abnormal bleeding; Treatment

1. Introduction Intrauterine devices (IUDs) are among the most widely used reversible contraceptive methods in the world and are used by more than 2 million women in the United States ☆ Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. ⁎ Corresponding author. Centers for Disease Control and Prevention, Division of Reproductive Health, MS K-34, NE, Atlanta, GA 30341. E-mail address: [email protected] (E.M. Godfrey).

0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.contraception.2012.09.006

(US) [1,2]. Copper-containing IUDs (Cu-IUDs) were introduced into worldwide markets in the late 1960s and are available in a variety of types, most of which are named for their shape and amount of copper on the device. Currently, the Copper 380A (TCu380A) is the sole CuIUD available in the US and is approved for use for 10 years, although effectiveness for up to 20 years has been shown [3]. The TCu380A is considered the most effective Cu-IUD [4]. Complaints of bleeding irregularities are common with Cu-IUD use and can lead to increased rates of method discontinuation [5]. A World Health Organization (WHO) trial conducted in South America demonstrated that women

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E.M. Godfrey et al. / Contraception xx (2012) xxx–xxx

receiving the multiload Cu-IUDs had significantly higher mean menstrual blood loss (MBL) for at least 12 months following insertion, whereas those who received the CuT200 or Cu-7 IUDs, which are more similar to the TCu380A, had an increase in MBL during the first 6 months of use that returned to preinsertion levels by 12–24 months [6]. Increased menstrual bleeding in the presence of a Cu-IUD is thought to be due to excessive prostaglandin release in the endometrial cavity [7]. Nonsteroidal anti-inflammatory drugs (NSAIDs) act as inhibitors of prostaglandin synthetase and help decrease the endometrial prostaglandin release, thereby potentially reducing MBL, even in the presence of Cu-IUDs [8]. Other medications may help treat heavy or prolonged menstrual bleeding during Cu-IUD use. The WHO's Selected Practice Recommendations for Contraceptive Use include a fibrinolytic agent, tranexamic acid, in addition to NSAIDs, as possible treatments for prolonged or heavy menstrual bleeding among Cu-IUD users [9]. This review sought to evaluate the evidence for effective therapeutic and preventive treatments for bleeding irregularities, such as intermenstrual spotting or heavy or prolonged menstrual bleeding, during Cu-IUD use.

alkaline hematin method (AHM), a procedure that assesses estimated blood loss on each sanitary pad and/or tampon [10], or the pictorial blood loss assessment chart (PBAC), a standardized chart with a scoring system that accounts for number and saturation of each sanitary pad or tampon [11]. We also reported on side effect information, where provided. 2.2. Assessment of study quality We summarized and systematically evaluated the evidence through the use of standard abstract forms [12]. The quality of each individual piece of evidence was assessed using the US Preventive Services Task Force grading system [13]. 2.3. Data synthesis Study results are summarized in Tables 1–3 and are organized by bleeding irregularity (i.e., spotting or light bleeding or heavy or prolonged bleeding) and by treatment type (therapeutic or prophylactic). Specific drug dosages and regimens, as well as methods used to measure MBL, are noted. We did not estimate overall summary measures of association due to the heterogeneity across identified studies with respect to study design, study population, Cu-IUD type and treatment type.

2. Materials and methods We searched the PubMed database for all articles (in all languages) published in peer-reviewed journals from inception of the database through March 2012 for evidence relevant to therapeutic and preventive treatments for bleeding irregularities among Cu-IUD users using the search strategy in Appendix A. Reference lists from identified articles, as well as key review articles, were hand-searched to identify additional articles. Articles that were in press in peer-reviewed journals and available online ahead of publication were also considered.

The search strategy in PubMed identified 1470 articles. After reviewing the titles and abstracts, and full articles when necessary, a total of 14 articles met inclusion criteria. We located three additional articles [14–16] cited by a 2006 Cochrane Review article [8]. Articles were not included if they were review papers, were not relevant to our objective, or included fewer than 50% of participants with Cu-IUDs and did not stratify results by IUD type.

2.1. Selection of studies

3.1. Therapeutic treatments

We reviewed titles and abstracts to identify relevant articles. We included articles that were relevant to treatments (therapeutic and prophylactic) for bleeding irregularities, including intermenstrual spotting, or heavy or prolonged menstrual bleeding during Cu-IUD use. Therapeutic treatment was defined as treatment for a current bleeding irregularity; prophylactic treatment was defined as treatment to prevent a bleeding irregularity in women who recently started using the Cu-IUD. Studies with multiple IUD types, including inert IUDs, were included in this review if at least 50% of the participants used Cu-IUDs or if results were stratified by IUD type. We examined outcomes related to spotting, MBL, number of menstrual bleeding days and proportion of subjects with bleeding irregularities. MBL was measured differently among the studies. Some studies measured MBL from self-report by study participants. Other studies used objective assessments, including the

3.1.1. Spotting or light bleeding Two studies examined the treatment of unscheduled spotting (Table 1) [17,18]. One nonrandomized comparison trial examined the effect of daily 1–2 mL intrauterine placements of one of two antifibrinolytic agents dissolved in saline solution, tranexamic acid (1 g/mL) or aprotinin (19 mg/mL) among 7 and 13 IUD users, respectively [17]. Treatments were initiated upon participant entry to the clinic (no other details provided) and given for one cycle. Spotting ceased after an average of 3 days of aprotinin treatment and an average of 2 days of tranexamic acid treatment [17]. No statistical comparisons for differences among the treatment groups were provided. In a randomized crossover trial among 18 Cu-IUD users with regular cycles, 14 of whom had intermenstrual spotting, Toppozada et al. [18] examined the effect of three oral NSAIDs: (1) indomethacin, 25 mg, four times daily; (2) flufenamic acid, 200 mg, three times

3. Results

Table 1 Treatment of spotting with Cu-IUD (chronological order) Study design

Population

Tauber et al., (1977) [17] Financial support from NIH, PARFR, Bayer Co.

Nonrandomized comparison Aprotinin dissolved in 0.9% SS (intrauterine placement), 19 mg/mL or tranexamic acid dissolved in 0.9% SS (intrauterine placement), 1 g/mL Intrauterine medications given 1x/day 1 cycle (tx only), Germany

1. Cessation of 20 women with Cu-IUD (type unspecified) with spotting spotting (self-report Duration of IUD use at not otherwise defined) enrollment: 0–11 months Age of participants: not stated

Toppozada et al. (1982) [18] RCT crossover Financial support Indomethacin (oral), 25 mg 4x/day; from WHO flufenamic acid (oral), 200 mg 3x/day; alclofenac (oral), 500 mg 3x/day; placebo Taken for 3 days at start of menses 4 cycles (2 placebo+2 tx cycles), Egypt

18 women with Cu-IUD users (CuT or Cu7); 78% (n=14) with spotting Duration of IUD use at enrollment: mean # of months ranged 15.3 to 16.5, depending on treatment group. Age of participants: 20–35 years

Outcome

1. Improved spotting (measured via menstrual diary)

Results

Strengths

Average # of daily intrauterine injections required to cease spotting episode: Aprotinin group (n=13): 3 daily injections Tranexamic acid group (n=7): 2 daily injections No improvement of Blinded spotting in any of the allocation treatment groups.

Weaknesses

Quality

II-1, poor No tx group assignment details No sample size calculation No statistical analysis No mention of how outcomes were measured No ITT reporting No sample size calculation Randomization scheme not described Subjective measurement of outcomes Outcome data from the menstrual diaries were not provided No ITT reporting No statistical analysis

I, poor

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Author, year, source of support

Abbreviations: ITT= intention-to-treat; SS=sterile saline; tx= treatment; NIH=National Institutes of Health; PARFR=Program for Applied Research on Fertility Regulation.

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Table 2 Treatment of heavy or prolonged bleeding with Cu-IUD (chronological order). Study design

Population

Outcome

Results

Tauber et al. (1977) [17] Financial support from NIH, PARFR, Bayer Co.

Nonrandomized comparison. Aprotinin dissolved in 0.9% SS (intrauterine placement), 19 mg/mL)/d or tranexamic acid dissolved in 0.9% SS (intrauterine placement), 1g/mL/d or SS (as control). Intrauterine medications given 1×/d. 1 cycle (tx only), Germany Cross-over (unspecified). Indomethacin (oral), 25 mg 3×/d ; flufenamic acid (oral), (dose not given); alclofenac (oral) (dose not given); placebo . Taken for 5 days at start of menses. 4 cycles (2 placebo + 2 tx cycles), Egypt

44 women with Cu-IUD (type unspecified) with increased menstrual bleeding per selfreport. Duration of IUD use at enrollment: 0–11 months. Age of participants: not stated

1. Length of menses (self-report not otherwise defined)

Average length of menses (days)

8 women with Cu-IUD (type unspecified) With increased menstrual bleeding per self-report. Duration of IUD use at enrollment: not stated Age of participants: not stated

1.MBL (measured by AHM)

Toppozada et al. (1980) [20] Financial support from WHO, Upjohn Company

Before tx After tx Percent of subjects reporting decrease in menses:

Strengths

Tranexamic acid (n=7)

Aprotinin (n=27)

9.3 (range: 5–14) 4.3 (range: 3–7) 54%, sustained 1–4 cycles

7.7 (range: 4–14) 4.3 (range: 3–7) 42%, sustained 2–7 cycles

Indomethacin or Flufenamic acid or alclofenac vs. placebo “Significant” reduction in menstrual flow for women on treatment when compared to placebo (no statistical tests reported).

Objective measurement of blood loss

Weaknesses

Quality

No sample size calculation No statistical analysis. No tx group assignment details. No mention of how outcomes were measured. Biased exposure: women w/menorrhagia prior to IUD insertion automatically assigned tranexamic acid tx group. No mention of LTF

II-1, poor

No sample size calculation No statistical analyses. No tx group assignment details. Number of participants receiving which NSAID not mentioned.

II-1, poor

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Author, year, source of support

Toppozada et al. (1982) [18] Financial support from WHO

Noncomparative pre-/postintervention trial. Mefenamicacid (oral), 500 mg 3×/d; placebo. Taken for 5 days max. at start of menses. 6 cycles (1&6 = pre/post-tx obs + 2&5= placebo + 3&4= tx cycles), Mexico

18 women with Cu-IUD (CuT or Cu7) with menses ranging 3–8 days, including 78% w/ intermenstrual spotting. Duration of IUD use at enrollment: mean # of months ranged 15.3 to 16.5, depending on treatment group. Age of participants: 20–35 years 12 women with Cu-IUD (TCu220C) with increased menstrual bleeding per selfreport. Duration of IUD use at enrollment: not stated. Age of participants: not stated

1.MBL (measured by AHM and menstrual diary)

Mean MBL per cycle (mL)

Indomethacin Flufenamic acid Alclofenac

Placebo

Medication

% MBL reduction

102.8 101.1 110.0

66.3 59.6 68.5

35.5 41.1 37.7

Placebo

Medication

% MBL reduction

104.6, SD 4.7

64.8, SD 4.6

38.0, SD 2.8§

Mean MBL (mL)

Standard Error

64.2 66.1

8.1 13.0*

58.5 59.0 91.4

6.9* 10.8* 19.2*

73.7

10.5*

Objective measurement of blood loss. Participants acted as own control.

No sample size calculation. Randomization scheme not described. Subjective measurement of outcomes. No ITT reporting. No description of blinding. Statistical analysis not described.

I, poor

Baseline observational cycle. Objective measurement of blood loss. Participants acted as own control. Identical looking tx and placebo pills.

Statistical analysis not described. No sample size calculation.

II-1, poor

Mean MBL of all cycles combined (mL), (pb.01)

§=pb.01

1.MBL (measured by AHM) 2. Monthly serum Hbg

Observation pre-tx Placebo pre-tx Treatment #1 Treatment #2 Placebo Post-tx Observation Post-tx

E.M. Godfrey et al. / Contraception xx (2012) xxx–xxx

Pedron et al. (1982) [15] Financial support from Kimberly Clark, Parke-Davis

RCT crossover. Indomethacin (oral), 25 mg 4×/d; flufenamic acid (oral), 200 mg 3×/d; alclofenac (oral), 500 mg 3×/d; placebo. Taken for 3 days at start of menses. 4 cycles (2 placebo + 2 tx cycles), Egypt

(*=N.S. compared to observation pre-tx) No differences found in Hbg concentrations, with values remaining within normal range.

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Table 2 (continued) Study design

Population

Outcome

Ylikorkala & Viinikka (1983) [24] Financial support from Medical Research Council, Academy of Finland

RCT crossover. Diclofenac sodium (oral), 50 mg 3×/d×1d, then 25 mg 3×/\d×4d; tranexamic acid (oral), 1.5g 3×/d; placebo. Taken for 5 days at start of menses. 5 cycles (alternate tx given for 2 consecutive cycles + 1 placebo cycle), Finland Nonrandomized crossover. Suprofen (oral), 200 mg 4×/d×1d, then 200 mg 3×/d; placebo. Taken for 7 days max at start of menses. 3 cycles (1 baseline observation + 1 tx+ 1 placebo cycle), Italy

19 women with IUD (18=Cu-IUD, type unspecified) with increased menstrual bleeding: 15 w/ N 80 mL & 4 w/70-80 mL blood loss. Duration of IUD use at enrollment: N 1 year. Age of participants: 25–44 years

1.MBL (measured by AHM) 2. Length of menses (measured with questionnaires)

28 women with Cu-IUD (Cu T or Cu7) with increased menstrual bleeding (not defined). Duration of IUD use at enrollment: 6–10 months. Age of participants: 21–33 years

1. Percent of participant reporting reduced MBL (measured by self-report, and using bleeding intensity scale)

Di Lieto et al., (1987) [19] Financial support not stated

Results

Baseline Placebo Diclofenac Tranexamic acid

Mean MBL (mL)

Standard Error

135.1 128.3 102.1 59.4

16.9 15.6 13.6 7.7

Compared to placebo, significant MBL reduction in diclofenac (pb.01) and tranexamic acid (pb0.001) cycles

Strengths

Weaknesses

Quality

Objective measurement of blood loss. Participants acted as own control. Compliance checked via pill count.

No sample size calculation. Randomization scheme not described. Part of outcomes measured through selfreport. Statistical analysis incompletely described. Active tx pills not identical.

I, fair

Baseline observational cycle. Participants acted as own control. No LTF

No sample size calculation. No tx group assignment details. Subjective measurement of outcomes. Incomplete description of blinding. No statistical analysis.

II-1, poor

Significant MBL reduction in tranexamic acid compared to diclofenac cycles (pb0.001) Length of menses (days) Standard Error Baseline Diclofenac #1 Diclofenac #2 Tranexamic acid #1 Tranexamic acid #2 Placebo

5.1 5.1 5.0 5.1 4.9 5.2

0.1 0.3 0.3 0.1 0.1 0.2

% participants experiencing reduction in MBL compared to baseline

Intense decrease Moderate decrease Slight decrease

Suprofen

Placebo

42.9% 35.7% 7.1%

0% 0% 7.1%

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Author, year, source of support

Pedron et al. (1987) [25] Financial support not stated

1.MBL (measured by AHM)

Group

N80 mL MBL (n=13)

60-80 mL MBL (n=16)

b60 mL MBL (n=24)

Pretreatment control cycle Treatment cycle1

96.4, SD 15.6 79.4, SD 36.3*

68.7, SD 7.3 63.5, SD 22.1*

Treatment cycle2 Treatment cycle3

102.1, SD 40.0* 96.5, SD 51.2*

70.6, SD 29.6* 84.1, SD 33.7*

Treatment cycle4

89.6, SD 53.3*

80.9, 34.2*

33.8, SD 11.8 54.6, SD 41.0 (pb.01) 51.1, SD 38.1* 62.6, SD 28.8 (pb.01) 58.1, SD 44.6 (pb.05)

Objective measurement of blood loss. Baseline observational cycle. Confounders considered.

No control group. No sample size calculation. Statistical analysis incompletely described.

II-1, poor

Objective measurement of blood loss. Participants acted as own control

Randomization scheme not well described. Statistical analysis incompletely described. No description of which participants were treated with tranexamic acid 3 months prior to this phase of study. Unclear blinding procedures

I, poor

(*=N.S. compared to pre-tx control cycle)

1.MBL (measured by AHM) 2. Percent of participant reporting continued prolonged MBL

Medication

Mean MBL (mL)

% MBL reduction compared to pre-tx

Tranexamic acid Flufenamic acid Aprotinin

99.4 89.7 122.5

13.2% § 20.7% § 2.8%*

(§=pb.001), (*=N.S. compared to pre-tx control cycle) Participants with continued prolonged MBL posttreatment Medication

% participants

p-value

Tranexamic acid Flufenamic acid Aprotinin

60.2 55.1 78.2

(pb.01) (pb.01) (pb .05)

Results of Chinese herb tx not reported

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RCT crossover. Tranexamic acid (IM injection) 200 mg 1×/d×3 days; Flufenamic acid (oral) 200 mg 3×/d ×5 days; Chinese herb 6 cycles (alternate tx given for 1 cycle, followed by no-tx cycle). For women who continued N80 mL MBL after 6 txbreak cycles (described above): aprotinin (intrauterine placement) 3–4 mL/hour×3 placements max, China

53 women with Cu-IUD (CuT220C) with increased menstrual bleeding per selfreport, divided into 3 groups: (1) MBL N80 mL, (2) MBL 60–80 mL, (3) MBL b60 mL. Duration of IUD use at enrollment: not stated. Age of participants: not stated 197 women with Cu-IUD (TCu220C or VCu200) or steel IUD with N80 mL MBL after prevention tx or no tx×3 mos. N 50% with Cu-IUD. Duration of IUD use at enrollment: 3 months. Age of participants: 20–39 years. 77 women continued to have N80 mL MBL after 6 tx-break cycles, and were treated with aprotinin for a 7th cycle.

E.M. Godfrey et al. / Contraception xx (2012) xxx–xxx

Chinese National IUD Research Working Group (1987) [21] Financial support not stated

Noncomparative pre-/postintervention trial. Aspirin (oral), 1000 mg 3×/d. Taken for 5 days max at start of menses. 5 cycles (1 baseline observation + 4 tx cycles), Mexico

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Table 2 (continued) Study design

Population

Outcome

Results

Strengths

Weaknesses

Quality

Pizarro et al. (1988) [14] Financial support from WHO, Parke-Davis

Non-randomized controlled trial. a Mefenamicacid (oral), 100 mg 3×/d; placebo. Groups: 1: premenses, medication to be taken ±2 d before menses or 2: menstrual cycle tx, medication to be taken 1st day of menses. Taken for 3 days at start of menses. 4 cycles (2 placebo + 2 tx cycles), Chile

40 women with IUD w/ mean MBL ≥ 60 mL 31/40 = Cu-IUD (Tcu220C or Tcu220 or Nova T) 9/40 = Lippes Loop w/increased menstrual bleeding measured during two placebo cycles. Duration of IUD use at enrollment: N 5 months. Age of participants: 18–39 years 180 women with Cu-IUD (“mostly” TCu220C) w/heavy or prolonged bleeding per selfreport. Duration of IUD use at enrollment: N 6 months. Age of participants: 24–45 years

1.MBL (measured by AHM)

Participants demonstrating positive treatment effect, mean MBL (mL)

Objective measurement of blood loss. Participants acted as own control. Baseline placebo cycles

No sample size calculation. Presented means among women with increased and decreased blood loss separately. Randomization scheme not described. No ITT reporting. Blinding, if any, not described

II-1, fair

Baseline observational cycles. Confounders considered

Randomization scheme not described. Blinding, if any, not described. No sample size calculation. No ITT reporting. No placebo treatment. Subjective measurement of outcomes

I, poor

Wu et al. (2000) [23] Financial support from WHO

RCT. Indomethacin (oral), 25 mg 2×/d×7 days at start of menses or Chinese herb. 9 cycles (3 tx + 3 pre+ 3 post observation cycles), China

Placebo Treatment % MBL reduction

Premenses treatment group (n=14, 70%)

Menses treatment group (n=16, 80%)

122.5 mL 91.7 mL § 25.1%

97.4 mL 72.2 mL § 25.9%

(§=pb.01)

1.MBL (measured by menstrual diary)

Indomethacin group (n=71) Cycle

Bleeding/ Spotting (days)

Mean menstrual length (days)

Pre-tx

38.9, SD 13.4 28.8, SD 9.6 30.2, SD 12.0

12.4, SD 5.1 9.5, SD 3.6 9.2, SD 5.0

Treat ment Post-tx

(p≤.001) Results of Chinese herb tx not reported

E.M. Godfrey et al. / Contraception xx (2012) xxx–xxx

Author, year, source of support

Mercorio et al. (2003) [22] Financial support not stated

RCT. Desmopressin (DDAVP) (intranasal) 300 mcg/d; Mefenamic acid (oral), 500 mg 3×/d. Taken for 5 days at start of menses. 5 cycles (2 baseline observation + 3 tx cycles), Italy

24 women with Cu-IUD (No Gravid M(R)) w/ increased menstrual bleeding using PBAC. Duration of IUD use at enrollment: N 6 months. Age of participants: 20–40 years

1.MBL (measured by PBAC scores) 2.Hemodynamic uterine changes (measured by uterine artery pressures)

Mean reduction in PBAC score

Mefenamic acid (n=12) DDAVP (n=12)

PBAC score (mean)

Percent reduction

95 (range: 1–169) 110 (range: 62–174)

45.7% §

Objective measurement of blood loss. No LTF. Baseline observational cycles

Randomization scheme not described. Blinding, if any, not described. No sample size calculation

I, fair

40.5% §

§=(pb.001) No significant differences of uterine artery pressure between groups

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Abbreviations: DDAVP=desmopressin; Hbg=hemoglobin; IM=intramuscular; ITT=intention-to-treat; LTF=loss to follow-up; max=maximum; NIH=National Institutes of Health; NS=not significant; obs= observation; PARFR=Program for Applied Research on Fertility Regulation; SD=standard deviation; SE=standard error; SS=sterile saline; tx=treatment; VCu=Copper V IUD. a Per Cochrane Review, Correspondence with author revealed alternate assignment to treatment groups.

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Table 3 Prevention of heavy or prolonged bleeding (chronological order) Study design

Population

Outcome

Results

Strengths

Weaknesses

Quality

Ylikorkala et al. (1978) [29] Financial support from Yrjo Jahnson Foundation; Medica Ltd. of Finland

RCT Tolfenamic acid (oral), 200 mg 3x/day; placebo Taken for 7 days at start of menses 3 cycles (tx/placebo only), Finland

160 women with Cu-IUD (TCu220) Duration of IUD use at enrollment: initiating Age of participants not stated

1. Length of menses post IUD insertion (measured with questionnaire 2. Menstrual bleeding (measured by # pads used and questionnaire

Mean length of menses (days)

Identical looking tx and placebo pill

No ITT reporting Subjective measure of outcomes Randomization scheme not described No sample size calculation

I. Poor.

Baseline observational cycle Objective measurement of blood loss Participants acted as own control Confounders considered No LTF

Randomization scheme not described No sample size calculation Unclear blinding procedures

I. Poor.

Objective outcome measures No LTF

No tx group assignment details Subject to bias with nontreatment group Statistical analysis not described No sample size calculation

II-1. Poor.

Immediate post IUD insertion

Blum & Pery (1984) [16] Financial support not stated

RCT crossover Ibuprofen (oral), 400 mg 4x/day; placebo Taken for 7 days max at start of menses 3 cycles (1 baseline obs+alternating 1 tx+ 1 placebo cycle), USA

10 women with Cu-IUD (Cu7, CuT220, or CuT380A) Duration of IUD use prior to enrollment: N5 months 18–33 years

1. MBL preand post-IUD insertion: (measured by AHM and menstrual diary) 2.Monthly serum Hbg

Nonrandomized intervention Indomethacin (oral), 25 mg 3x/day; Flufenamic acid (oral), 125 mg 3x/day; Naproxen (oral), 250 mg 3x/day; no treatment Taken for 3 days at start of menses 4 cycles (tx/no tx only), Israel

115 women with IUD, 77 w/ Cu-IUD (Cu7, CuT200, or NovaT380) Duration of IUD use at enrollment: initiating 23–45 years

1. Change in serum Hbg, Hct and iron preand post-IUD insertion

Placebo (n=62)

3.9, SD 2.7

4.5, SD 2.4

pb0.10 Mean # of pads used daily

Immediate post IUD insertion pb0.001 Subsequent 2 cycles Roy & Shaw (1981) [28] Financial support from Upjohn Co.

Tolfenamic acid (n=60)

Tolfenamic acid (n=60)

Placebo (n=62)

2.1, SD 0.9

3.5, SD 2.5

5.2, SD 1.1

6.2, SD 2.0

pb0.0005 Mean reduction in MBL (mL) Ibuprofen initially

Placebo initially

Baseline placebo cycles

3.3 mL reduction, SE 7.5 (NS)

Placebo treatment cycles

10.42 mL reduction, SE 8.5 (pb.05)

0.98 mL increase, SE 4.7 (NS) 8.52 mL reduction, SE 3.6 (pb.05)

Change in serum blood values pre to post IUD insertion

Hbg

pre post

Iron

pre post

Hct

pre post

Treatment group (n=52)

No treatment group (n=63)

12.9g/dl 13.3g/dl pb.05 115.5mcg/dl 124.0mcg/dl pb.02 unchanged

12.8g/dl 11.5g/dl pb.01 115.0mcg/dl 84.4mcg/dl pb.01 37.5% 33.9% pb.01

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Author, year, source of support

Markarinen & Ylikorkala (1986) [27] Financial support from Emil Aaltonen Foundation; Orion Corporation Research Foundation; Finland's Cultural Fund and Medipolar; Farmos Group

RCT Ibuprofen (oral), 400 mg 3x/day; placebo Taken for 10 days max at start of menses 5 cycles (2 baseline obs+3 tx/placebo cycles), Finland

28 women with Cu-IUD (Fincoid 350 or ML Cu375) Duration of IUD use at enrollment: initiating 24–45 years 2 subjects used OCPs w/1 spontaneous cycle prior to enrollment

1. MBL, preand post-IUD insertion (measured by AHM and participant self-reported questionnaire

Median MBL (mL)

Preinsertion Postinsertion Median % increase in MBL

Placebo (n=12)

38, range 16-102 47, range 3-128 (pb.05)** 2%, range 51 - +192%

38, range 4-99 57, range 12-213 (pb.05)* 74%, range –4 - + 200%

Baseline observational cycles Objective measurement of blood loss Compliance checked via pill count

No sample size calculation provided Statistical analysis incompletely described Unclear blinding procedures Randomization scheme not described

I. Fair.

Baseline observational cycle Objective measurement of blood loss

Randomization scheme not described Statistical analysis incompletely described Subject to bias with nontreatment group Number of subjects assigned to each group not reported No sample size calculation

I. Poor.

(p b.01)* Mean length of menses (days)

Randomized intervention Tranexamic acid (oral), 1 g 2x/day; no treatment Taken for 5 days at start of menses 4 cycles (1 baseline obs+3 tx/no tx cycles), China

756 IUD (512 Cu-IUD (TCu220C or VCu200) Duration of IUD use at enrollment: initiating 20–39 years

1. MBL, preand post-IUD insertion (measured by AHM) 2. Proportion of participants reporting continued MBL

Treatment (n=16)

Placebo (n=12)

5.4, SD 1.2

5.5, SD 1.2

6.2, SD 1.6

6.4, SD 1.6

(pb.05)*

(pb.05)*

*compared with the value prior to IUD insertion **compared with placebo Mean MBL (mL)

Treatment cycles 1-3

Treatment (n=375)

No treatment (n=380)

65.7, SE 1.8

81.8, SE 2.7

% of participants with mean MBL N80mL, by cycle Cycle 1 2 3

TCu220c

VCu200

Tx 23, n=108 25, n=112 24, n=114

Tx 37, n=94 27, n=98 23, n=97

No Tx 36, n=109 35, n=111 26, n=109

No Tx 60, n=107 46, n=106 38, n=105

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Preinsertion Postinsertion

Chinese National IUD Research Working Group (1987) [21] Financial support not stated

Treatment (n=16)

(continued on next page)

11

12

Table 3 (continued) Study design

Population

Outcome

Results

Hubacher et al. (2006) [26] Financial support from NIH

RCT Ibuprofen (oral) 400 mg 3x/day; placebo Taken for 5 days max at start of menses 6 cycles (tx/placebo only) Follow-up @ 1 year, Chile

2019 Cu-IUD (CuT380A) Ibuprofen 1011 Placebo 1008 Duration of IUD use at enrollment: initiating 18–49 years

1.IUD removal within 12 months of insertion for any reason

Removal of IUD w/in 1 year follow-up

RCT Tranexamic acid (oral), 1g 2 x/day; tranexamic acid 500 mg 2x/day; placebo Taken for 5 days at start of menses 4 cycles (1 baseline obs+3 tx/placebo cycles), China

175 initiating Cu-IUD (VCu200) Duration of IUD use at enrollment: initiating 20–40 years

Lin et al. (2007) [30] Financial support from Daiichi Pharmaceutical Co. Ltd., National Population and Family Planning Commission

Ibuprofen

Placebo

n=257/929 (27.7%)

n=246/926 (26.6%)

Probabilities of removal by reason (0-12 months) Expulsion Any pain/bleeding 1. MBL, pre- and post-IUD insertion: (measured by PBAC scores and by AHM

Ibuprofen 0.13; 95% CI 0.10-0.15 0.13; 95% CI 0.11-0.15

Placebo 0.14; 95% CI 0.11-0.16 0.11; 95% CI 0.09-0.13

Odds of MBL N 80 mL post IUD insertion MBL Measure

Tranexamic acid 2g/d

Tranexamic acid 1 g/d

AHM

OR 0.21; 95% CI 0.07-0.62 OR 0.46; 95% CI 0.25-0.86

OR 0.32; 95% CI 0.11-0.95 OR 0.80; 95% CI 0.41-1.54

PBAC

(placebo=referent)

Strengths

Weaknesses

Quality

Allocation concealment Blinding procedures described Sample size calculation provided ITT principles applied Confounders considered

No assessment on reduction of blood loss

I. Good.

Baseline observational cycle Per protocol population tracked, analyzed and compared with the protocol violation population Objective measurement of blood loss

Randomization scheme not described No sample size calculation

I. Fair.

Abbreviations: Hbg=hemoglobin; Hct=hematocrit; ITT=intention-to-treat; LTF=loss to follow-up; NS=not significant SD=standard deviation; SE=standard error; Tx=treatment; VCu=Copper V IUD.

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Author, year, source of support

E.M. Godfrey et al. / Contraception xx (2012) xxx–xxx

daily; or (3) alclofenac, 500 mg, three times daily on intermenstrual spotting, taken for 3 consecutive days at start of menses. The treatments reportedly did not improve intermenstrual spotting, although outcome data from the menstrual diaries were not provided. 3.1.2. Heavy or prolonged menstrual bleeding 3.1.2.1. Treatment with NSAIDs. Ten studies examined oral ingestion of NSAIDs, including aspirin, for the treatment of heavy or prolonged menstrual bleeding among Cu-IUD users and compared outcomes from these treatments to outcomes from a placebo or baseline cycle (Table 2) [14,15,18–25]. Three trials examined the use of indomethacin [18,20,23], three examined mefenamic acid [14,15,22], and three examined flufenamic acid [18,20,21]. Other NSAIDs used in the reported trials included alclofenac [18,20], suprofen [19], diclofenac sodium [24] and aspirin [25]. All of the studies examined MBL as a primary outcome, either by using a procedure such as the AHM [14,15,18,20,21,24,25] or PBAC scores [22], or by using a menstrual diary or questionnaire [19,23]. Eight of the 10 NSAID studies reported clinically improved bleeding with treatment. In a randomized trial by Toppozada et al. [18] that studied the effect of one of three NSAIDs: (1) indomethacin, 25 mg, four times daily; (2) flufenamic acid, 200 mg, three times daily; or (3) alclofenac, 500 mg, three times daily, taken for 3 days at start of menses for four cycles, investigators reported an overall reduction in MBL relative to placebo of 38%, SD 2.8 (pb.01). Differences between the treatment groups were not detected with percent reduction in MBL ranging from 35.5% to 41.0% (pN.05). An earlier study by Toppozada et al. [20] that used the same oral NSAIDs [indomethacin, 25 mg, three times daily for 5 days; flufenamic acid; alclofenac (dosages and regimens not given)], eight Cu-IUD users with self-reported menorrhagia at enrollment had a consistent and significant reduction in posttreatment MBL relative to placebo cycles. The results were only shown graphically, with no reporting of statistical tests or analytic method. Two randomized controlled trials (RCTs) conducted in China assessed the effect of either indomethacin or flufenamic acid and compared the treatments to pretreatment baseline cycles. One RCT enrolled 180 Cu-IUD users who reported heavy or prolonged bleeding (N7 days), 90 of whom took indomethacin, 25 mg, twice daily for 7 days at start of menses for three treatment cycles [23]. Participants recorded bleeding before, during and after treatment in menstrual diaries. Compared to pretreatment cycles, indomethacin treatment showed a significant reduction in the number of bleeding/spotting days (pretreatment: 38.9 days, SD 13.4; during treatment: 28.8 days, SD 9.6; p≤.001) and mean bleeding/spotting length (pretreatment: 12.4 days, SD 5.1; during treatment: 9.5 days, SD 3.6; p ≤ .001). Similar differences were seen between the pre- and posttreatment

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cycles. The Chinese Research Working Group [21] conducted a randomized crossover study in which both steel and Cu-IUD users were assigned to one of three treatment groups, including flufenamic acid, 200 mg, three times daily for the first 5 days of menses, Chinese herb, and intramuscular (IM) injection with tranexamic acid, 200 mg, given once daily for 3 consecutive days at start of menses. Participants included 197 women who had mean pretreatment MBL N80 mL following a 3-month prophylactic study phase in which they had taken oral tranexamic acid or no treatment following IUD insertion. These women were randomly assigned to each of the three treatments for one cycle with a treatment-free cycle in between. The flufenamic acid treatment cycles demonstrated a significant reduction in MBL of an average of 20.7 mL compared to the pretreatment cycles (pb.001). Three studies [14,15,22] examined the effect of mefenamic acid; two small studies reported positive findings, and one small study noted no significant difference with treatment. Pizarro et al. [14] alternately assigned 40 IUD users with N60 mL mean MBL during two placebo cycles to mefenamic acid, 100 mg, three times daily for 3 days, starting (a) several days prior to menstruation or (b) the first day of menstruation [14]. Compared to the placebo cycles, MBL was significantly reduced (pb.01) among most participants regardless of when treatment was initiated [14]. An RCT in which 24 Cu-IUD users with menorrhagia were assigned to mefenamic acid, 500 mg, three times daily, or intranasal desmopressin (an antidiuretic), 300 mcg, once daily, for the first 5 days of menses for three treatment cycles found a significant reduction in mean MBL (45.7%) among the 12 participants randomized to the mefenamic acid group (pb.001) compared with pretreatment baseline values [22]. In contrast to these positive findings, a small prospective trial of 12 Cu-IUD users found no significant reduction in bleeding with mefenamic acid use [15]. This study examined two treatment cycles with mefenamic acid, 500 mg, three times daily for the first 5 days of menses, which were preceded and followed by placebo and posttreatment cycles. No significant reduction in MBL was detected during treatment cycles, and no differences in hemoglobin were reported [15]. Di Lieto et al. [19] examined the use of suprofen, 200 mg, four times daily for the first day, followed by 200 mg, three times daily for up to 6 days at start of menses, among 28 CuIUD users who were nonrandomly assigned to either suprofen or placebo for 1 month following a 1-month baseline observation cycle. Changes in MBL were assessed by self-report as “intense,” “moderate” or “slight,” not otherwise defined. During suprofen treatment, 42.9% of the participants reported an “intense” decrease in MBL, 35.7% reported a “moderate” decrease in MBL and 7.1% reported a “slight” decrease in MBL compared to the baseline cycle. In contrast to these findings, 7.1% of subjects reported a “slight” decrease in blood loss and none reported an “intense” or “moderate” decrease during the placebo

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cycle. Statistical comparisons for differences between treatment and placebo cycles, or baseline and treatment cycles were not provided. Ylikorkala and Viinikka [24] conducted a randomized trial comparing diclofenac sodium, 50 mg, three times daily for the first day, followed by 25 mg, three times daily for 4 days at start of menses, and an oral antifibrinolytic agent, tranexamic acid, for five cycles among 19 Cu-IUD users; the alternate treatment regimens were given for two consecutive cycles each, followed by placebo for one cycle. Compared with placebo, treatment with diclofenac sodium resulted in a statistically significant reduction in MBL by 20% to a mean of 102.1 mL (SE 13.6) from 128.3 mL (SE 15.6; pb.01) [24]. Pedron et al. [25] conducted a noncomparative pre-/ postintervention trial to examine the effect of aspirin on bleeding in which 53 Cu-IUD users with increased menstrual bleeding were assigned to aspirin, 1000 mg, three times daily for maximum of 5 days at start of menses, for four treatment cycles. The aspirin slightly, but not significantly, decreased menstrual bleeding among 13 women with pretreatment baseline hypermenorrhea (N80 mL MBL). Statistically significant increases in blood loss occurred with treatment among women whose baseline MBL was b60 mL [25]. 3.1.2.2. Treatment with antifibrinolytic agents. Three studies examined the use of antifibrinolytic agents for the treatment of heavy or prolonged menstrual bleeding. Routes of treatment administration included IM injection, intrauterine placement and oral ingestion [17,21,24]. Two studies measured MBL using a procedure such as the AHM [21,24], whereas one study used participant self-report (not otherwise specified) [17]. Tauber et al. [17] conducted a nonrandomized trial of the effect of daily 1–2 mL intrauterine placements of one of two antifibrinolytic agents dissolved in saline solution, tranexamic acid (1 g/mL) or aprotinin (19 mg/mL), among 44 CuIUD users. Participants were given one of the two agents or sterile saline (as control) for 1 to 3 consecutive days during menstruation or just prior to onset of menstruation for one cycle. In the tranexamic acid group, 54% reported decreased length of menstruation, and treatment effects persisted for one to four cycles. In the aprotinin group, 42% reported decreased length of menstruation, with treatment effects persisting for two to seven cycles. No reduction in length of menstruation was reported for the control group, and some increase in uterine bleeding was noted. The authors did not provide statistical comparisons for differences among the treatment and control groups. In the randomized trial by the Chinese Research Working Group, tranexamic acid, given as a 200 mg IM injection once daily for 3 consecutive days at onset of menses, was one of three treatments during one phase of the trial. Other treatments given included oral flufenamic acid and a Chinese herb. Treatment cycles with tranexamic acid demonstrated a significant reduction in MBL of 13% compared to pretreatment cycles (pb.001) [21]. The proportion of participants

with prolonged bleeding immediately after the tranexamic acid treatment cycles was also reduced (82% at baseline compared to 60% after tranexamic acid treatment; pb.01). Women who still had menorrhagia (n=77) despite three separate treatment-break cycles were subsequently treated with intrauterine placements of another fibrinolytic agent, aprotinin (3–4 mL/h, up to three intrauterine placements, method not described). The reduction in mean MBL during the aprotinin treatment cycle was 2.8%, which was reportedly not significant compared to the pretreatment cycles, although a significant reduction was reported for the proportion of participants with prolonged bleeding immediately after treatment (95% at baseline compared to 78% after treatment, pb.05). In the RCT crossover study by Ylikorkala and Viinikka [24], four treatment cycles with oral tranexamic acid, 1.5 g, three times daily for 5 days at start of menses, demonstrated a significant reduction in MBL relative to the placebo cycle (59.4 mL, SE 7.7 versus 128.3 mL, SE 15.6; pb.001) and relative to the NSAID, diclofenac sodium, (102.1 mL, SE 13.6; pb.001).

3.1.2.3. Treatment with antidiuretics. Mercorio et al.[22] (study detailed earlier) examined the use of a synthetic form of vasopressin, intranasal desmopressin, 300 mcg, once daily for the first 5 days of menses, for three treatment cycles and found a significant reduction in PBAC scores in the vasopressin group compared with baseline (pb.001). 3.2. Preventive treatments 3.2.1. Prevention with NSAIDs We identified five studies that tested NSAIDs, all taken orally, for the prevention of heavy or prolonged menstrual bleeding among Cu-IUD users; three included ibuprofen, one included tolfenamic acid, and one included several different types of NSAIDs (Table 3) [16,26–29]. Three randomized trials examined MBL as the primary outcome, measured by a procedure such as the AHM [27,28] or by sanitary pad counts and participant questionnaires [29]. One nonrandomized trial examined pre- and post-IUD insertion change of serum hemoglobin, hematocrit and iron levels [16], and one randomized study examined IUD removal rates as the primary outcome [26]. In two of these NSAID studies, investigators reported improved bleeding or hemoglobin levels with treatment, although the third study reported no difference in IUD continuation at 1 year between participants who took ibuprofen and those who took placebo for the first 6 months after IUD placement. Ylikorkala et al. [29] randomized 160 new Cu-IUD users to tolfenamic acid, 200 mg, three times daily for 7 days at start of menses, or placebo for three consecutive cycles. Overall, the treatment group had fewer bleeding days than the placebo group, although the difference was not significant (pb.10).

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Three randomized trials examined the use of ibuprofen prophylactically. Markarinen and Ylikorkala [27] enrolled 28 new Cu-IUD users to placebo or ibuprofen, 400 mg, three times daily for a maximum of 10 days at start of menses, for three consecutive cycles. Median values of MBL postinsertion were significantly higher among women in the placebo group compared to those in the ibuprofen group (placebo: 57 mL, range 12–213; ibuprofen: 47 mL, range: 3–128; pb.05). When compared to the preinsertion/pretreatment values, MBL increased by 74% in the placebo group, but only 2% in the ibuprofen group (pb.01). Roy and Shaw [28] conducted a crossover trial in which 10 women who had been using the Cu-IUD for at least 5 months were randomized either to placebo or treatment with ibuprofen, 400 mg, four times daily for 7 days maximum at onset of menses, for one cycle following one baseline observation cycle and then alternated treatment assignments for a subsequent cycle. Ibuprofen produced a significant decrease in MBL, with an overall reduction of 25% for Cu-IUD users (pb.05). Hubacher et al. [26] examined the use of ibuprofen, 400 mg, three times daily for 5 days maximum at onset of menses, versus placebo among 2019 first-time Cu-IUD users for the first six cycles postinsertion. Investigators found that 6-month treatment with ibuprofen did not lead to a significant difference in cumulative probability of removals at 1 year due to dysmenorrhea or increased MBL [probability of removal was .13 (95% CI .11–.15) for ibuprofen group versus .11 (95% CI .09–.13) for placebo group] [26]. A nonrandomized intervention trial among 115 Israeli women evaluated the change in serum hemoglobin, hematocrit and iron levels of either no treatment (n=63) or one of several NSAIDs (n=52): (a) indomethacin, 25 mg, three times daily; (b) flufenamic acid, 125 mg, three times daily; and (c) naproxen, 250 mg, three times daily for 3 days at start of menses, for a total of four cycles following IUD insertion [16]. Compared to baseline, the investigators found a statistically significant increase in mean levels of serum hemoglobin (12.9 g/dL preinsertion to 13.3 g/dL postinsertion; pb.05) and iron (115.5 mcg/dL preinsertion to 124 mcg/dL postinsertion; pb.02) in each of the NSAID groups. In the untreated group, there was a statistically significant decrease in mean levels of serum hemoglobin (12.8 g/dL preinsertion to 11.5 g/dL postinsertion; pb.01) and iron (115.5 mcg/dL preinsertion to 84 mcg/dL postinsertion; pb.01) compared to baseline. None of the findings was clinically significant. The authors note that NSAID treatment prevented excessive bleeding, although uterine bleeding was not measured directly in this study. Statistical methods used in this study were not reported [16]. 3.2.2. Prevention with antifibrinolytic agents Two randomized trials examined the use of an oral antifibrinolytic agent, tranexamic acid, for the prevention of

15

heavy menstrual bleeding for three consecutive cycles after IUD insertion. Both of these studies examined MBL as the primary outcome using a method such as the AHM [21,30]; one of these studies also included PBAC scores as measurement for MBL [30]. Both studies reported significant reductions in blood loss compared to placebo or no treatment. One trial was an intervention trial in which 756 women initiating either a steel or Cu-IUD were randomized to either tranexamic acid, 1 g twice daily for 5 days at onset of menses, for three cycles following IUD placement, n= 375, or no treatment, n=380 [21]. MBL was consistently lower in the treatment group during each cycle after IUD placement (65.7 mL, SE 1.8 per cycle versus 81.8 mL, SE 2.78 mL per cycle, treatment and no treatment groups, respectively), as were the proportion of subjects with MBL N80 mL (Table 3). An RCT by Lin et al.[30] examined the use of two different doses of tranexamic acid, 500 mg or 1 g, twice daily for 5 days at start of menses, for three treatment cycles versus placebo in 175 women initiating Cu-IUD. Cycle-specific results showed increased MBL in all groups after IUD insertion, followed by a significantly greater decline in MBL during the second and third cycles for the tranexamic acid 2-g/d group, relative to placebo (pb.05; MBL values not reported). The overall mean reduction in MBL compared to placebo was 19.9 mL for tranexamic acid 1 g/d and 23.8 mL for tranexamic acid 2 g/d (pb.05); no significant difference was detected between treatment groups. Nineteen participants in the trial were not compliant with the medication; a reanalysis with the perprotocol population (defined as having taken N80% of prescribed pills) did not show a difference in the effect measures between treatment and placebo groups (data not shown in the report). 3.3. Side effect profiles The majority of studies reported side effect information, stating that participants either reported no side effects or had only mild symptoms. Symptoms reported for participants taking NSAIDs were typically associated with headache or gastrointestinal discomfort [14,18– 20,23, 24,28,29], although one study reported that 4 of 28 participants reported tiredness, irritability and sweating when taking ibuprofen [27]. Only two of the four studies examining antifibrinolytic agents reported side effects [17,24], and one stated that 12 of 19 participants complained of gastrointestinal disturbances when taking tranexamic acid [24]. No adverse events were noted in any of the studies, although four studies did not report on side effects or adverse events from treatment medication(s) [15,21,26,30]. Two studies, both by the same investigator, reported discontinuations due to medication side effects: one discontinuation occurred from a participant taking diclofenac sodium who developed

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lower extremity edema; three discontinuations occurred from participants taking tolfenamic acid, but specific symptoms associated with these discontinuations were not reported [24,29].

4. Discussion This systematic review found NSAIDs to be the most widely studied medications for blood loss reduction in the presence of a Cu-IUD; evidence indicated that these medications can reduce menstrual bleeding for a current bleeding episode and may prevent heavy or prolonged menstrual bleeding. Our findings are consistent with a Cochrane Review that found NSAIDs reduce bleeding with IUD use [8]. Most of the side effects reported by the studies of NSAIDs were mild, although two studies mentioned a small number of discontinuations due to side effects. Other, less widely studied, but possibly effective treatments included in this review were antifibrinolytic agents, which help prevent the disintegration of blood clots. A study of the use of oral tranexamic acid to stop a current bleeding episode was limited to 19 subjects for two consecutive cycles in a trial of fair quality; the majority complained of mild side effects, mostly gastrointestinal in nature, such as diarrhea or lower abdominal pains, and no adverse events were reported [24]. Other formulations of tranexamic acid treatments mentioned in this review, including intrauterine and IM administration, are not commonly used in the US. As a preventive measure, data from two studies (Level I, fair to poor), in which approximately 450 subjects were treated with oral tranexamic acid, demonstrated significant reductions in heavy and prolonged menstrual bleeding, although safety profiles were not assessed by the investigators [21,30]. Antifibrinolytics are widely used outside the US [31]. Tranexamic acid is listed by the WHO as an “essential medicine,” medications that are considered to satisfy the priority needs of a population and are selected based on public health relevance, effectiveness and safety [32]. Within the US, tranexamic acid use is more limited, in part because of its high cost, but also because of a Food and Drug Administration warning that it is contraindicated in women with active thromboembolic disease or with a history or intrinsic risk of thrombosis or thromboembolism [33]. Deaths have been reported in trials that included tranexamic acid use among cardiac surgery patients at high risk of perioperative mortality [34], but a Cochrane Review on its use to treat heavy menstrual bleeding concluded that oral administration of antifibrinolytic therapy was not associated with an increased risk for adverse events [35]. The antidiuretic desmopressin, which acts as a vasoconstrictor, was shown in one study to have promise in treating heavy or prolonged menstrual bleeding with Cu-IUD use, although the study was limited

to only 12 subjects [22]. In a comprehensive review of nonhormonal treatments for heavy menstrual bleeding among women with underlying bleeding disorders, three separate studies examined intranasal vasopressin, a similar medication to desmopressin, demonstrating reductions in MBL from 17%–50% [36]. Additional studies are needed to further assess the effectiveness and safety of antifibrinolytic or antidiuretic treatments for bleeding irregularities among Cu-IUD users. The studies included in this review have several limitations. Many of the trials had significant design weaknesses such as using self-report of bleeding irregularities for eligibility entrance criteria [15,17–21,23,25], subjective measurements of outcome data [17,19,21, 23,24,27,29], missing or insufficient a priori sample size calculations [14–25,27–29] and failure to describe randomization scheme and blinding procedures [14,16– 24,27–30]. Statistical methods were either not mentioned or lacked adequate information in many studies [15– 21,24,25,27]. Additional limitations include the use of treatment medications not currently approved for use in the US [16–21,29], as well as use of Cu-IUDs not currently available in the US, indicating that treatment responses may not necessarily be applicable to women who use the TCu380A. Another limitation was the paucity of data in most studies reporting on participant satisfaction, duration of treatment effects and participant Cu-IUD continuation. These outcomes are important, particularly if the purpose of treating bleeding irregularities is to positively impact the long-term use of the Cu-IUD. Only one study reported on long-term use and found that ibuprofen treatment, when taken to prevent heavy or prolonged menstrual bleeding, did not affect Cu-IUD continuation [26]. Additional studies are needed that measure Cu-IUD continuation after treatment of a current bleeding episode. The present systematic review is limited by heterogeneity of the study designs, variability of medications and dosages used, as well as inadequate sample sizes. While this review can make broad conclusions about various classes of drugs, future studies should focus on more rigorous study design with adequate sample sizes and standard treatment regimens. In conclusion, limited evidence is available for treatment of bleeding irregularities that occur during CuIUD use. “Level I to II-1, fair to poor” evidence suggests that NSAIDs may be effective in treating bleeding irregularities. “Level I to II-1, fair to poor” evidence suggests that tranexamic acid or intranasal desmopressin may also be effective, although these treatments were only studied in a small number of participants and their safety has not been well documented. “Level I to II-1, fair to poor” evidence suggests that NSAIDs and antifibrinolytics may prevent bleeding irregularities in Cu-IUD users, although “Level I, good” evidence suggests that preventive NSAID use does not impact continuation of the Cu-IUD.

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Acknowledgments The authors wish to thank Sarah Prager, M.D., M.A.S., for her critical review of this manuscript. Appendix A. Search strategy for bleeding irregularities in women with Cu-IUD (((treatment OR manage OR control)) OR ("AntiInflammatory Agents, Non-Steroidal"[Mesh])) AND (IUD [All Fields] OR ("intrauterine devices"[MeSH Terms] OR "intrauterine devices"[All Fields] OR "intrauterine device"[All Fields]) OR ("intrauterine devices"[MeSH Terms]) OR ("intrauterine"[All Fields] AND "devices"[All Fields] OR "intrauterine devices"[All Fields]) OR ("intrauterine devices/methods"[Mesh Terms]) OR ("intrauterine contraception"[All Fields] OR IUDC[All Fields])) AND (("haemorrhage"[All Fields] OR "hemorrhage"[MeSH Terms] OR "hemorrhage"[All Fields]) OR ("hemorrhage"[MeSH Terms] OR "hemorrhage"[All Fields] OR "bleeding"[All Fields]) OR ("menorrhagia"[MeSH Terms] OR "menorrhagia"[All Fields]) OR ("metrorrhagia"[MeSH Terms] OR "metrorrhagia"[All Fields]) OR ("metrorrhagia"[MeSH Terms] OR "metrorrhagia"[All Fields] OR "spotting"[All Fields]) OR "abnormal menstruation"[All Fields] OR "bleeding irregularities"[All Fields]). References [1] d'Arcangues C. Worldwide use of intrauterine devices for contraception. Contraception 2007;75:S2–7. [2] Mosher WD, Jones J. Use of contraception in the United States: 1982– 2008. Vital Health Stat 2010;23:1–4. [3] Sivin I. Utility and drawbacks of continuous use of a copper T IUD for 20 years. Contraception 2007;75:S70–5. [4] Kulier R, O'Brien PA, Helmerhorst FM, Usher-Patel M, D'Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev 2007:CD005347. [5] Sivin I, Stern J, Diaz S, et al. Rates and outcomes of planned pregnancy after use of Norplant capsules, Norplant II rods, or levonorgestrelreleasing or copper TCu 380Ag intrauterine contraceptive devices. Am J Obstet Gynecol 1992;166:1208–13. [6] Andrade AT, Pizarro E, Shaw Jr ST, et al. Consequences of uterine blood loss caused by various intrauterine contraceptive devices in South American women. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction. Contraception 1988;38:1–8. [7] Ylikorkala O. Prostaglandin synthesis inhibitors in menorrhagia, intrauterine contraceptive device-induced side effects and endometriosis. Pharmacol Toxicol 1994;75(Suppl 2):86–8. [8] Grimes DA, Hubacher D, Lopez LM, Schulz KF. Non-steroidal antiinflammatory drugs for heavy bleeding or pain associated with intrauterine-device use. Cochrane Database Syst Rev 2006:CD006034. [9] World Health Organization. Selected practice recommendations for contraception use. 2nd ed. Geneva: WHO; 2004. [10] Newton J, Barnard G, Collins W. A rapid method for measuring menstrual blood loss using automatic extraction. Contraception 1977; 16:269–82. [11] Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990;97:734–9.

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