Description of the condition
Over the past 30 years, the number of users of progestin-only methods of contraception has been increasing steadily worldwide and is estimated to be over 20 million. The method most widely used is the injectable depot medroxy-progesterone acetate (DMPA), first registered in the late 1960s in some countries. Its approval for contraceptive use by the United States Food and Drug Administration in 1992 increased access to the method worldwide, through new registrations; approximately 13 million women worldwide use DMPA for contraception. The other progestin-only injectable contraceptive currently available, norethisterone enanthate, is estimated to be used by fewer than one million women.
Additional progestin-only contraceptive methods are based on several delivery systems: subcutaneous implants, intra-uterine systems, vaginal rings and oral preparations. Five implant systems are available to family planning programmes; the most widely-used of these was the six capsule levonorgestrel-releasing implantable system, Norplant. This method was introduced in 1983, and has been used by approximately six million women; post-registration studies have demonstrated that the method is highly effective over a period of seven years. Its manufacture was discontinued in 2002.The two-rod levonorgestrel-releasing implantable system, Jadelle, is effective for five years and was first registered for this length of use in the year 2000. Two generic products, designed to imitate the performance of these two implants, are made in China and are known as Sino-implant (I) and (II), respectively. A single-implant system that has been available since 1997, Implanon releases etonogestrel and is effective for a period of 3 years and is used by approximately six million women worldwide. The levonorgestrel-releasing intra-uterine system, Mirena, has been available since 1990 and is currently used by around ten million women worldwide. The progesterone-releasing vaginal ring, Progering, designed for use by breast feeding women, has been available in limited markets since the late 1990s. Use of progestin-only oral preparations remains limited, despite being appropriate for lactating women and others who do not tolerate estrogens. Other progestin-only methods are being developed, such as transdermal patches and new injectable, implantable and intra-uterine systems.
Progestin-only contraceptive methods are highly effective ,safe and the long-acting properties of several delivery systems facilitate their use. However, despite differences in their primary mechanisms of action, all induce major uterine bleeding disturbances in a significant number of users. Data from clinical trials demonstrate that, at one year of use, fewer than 10% of DMPA and Mirena users and only 25% of Norplant users experience regular monthly bleeding, while others experience a variety of patterns ranging from infrequent bleeding and amenorrhea to irregular, frequent or prolonged bleeding. These patterns are all classified as breakthrough bleeding and have been discussed in several publications (Newton 1994, Fan 1996, Suvisaari 1996, Affandi 1998, Fraser 1998,). This side effect is the primary reason that women give for discontinuing use of these methods and accounts for 40-70% of termination from clinical trials (d'Arcangues 1992, Datey 1995,; Adeyemi 2012). There seem to be great variations in the tolerance that women have for these disturbances. In a multicenter clinical trial of DMPA, for example, users in Egypt, Jamaica and Thailand reported similar rates of amenorrhea. In Egypt, 27% of women discontinued DMPA use for this reason, while none did so in Thailand or Jamaica (Said 1987).
Individual women respond differently to the use of progestin-only methods. Bleeding effects may also vary according to the type of progestin and the dose. With Norplant use, prolonged and irregular breakthrough bleeding is usually at its worst during the first 12 months of use, becoming more regular thereafter. With DMPA, users also start by experiencing prolonged and irregular bleeding, but later on this pattern is replaced by increasing periods of amenorrhea. A reasonable clinical goal would be to provide an intervention to assist women in managing any irregularities in bleeding - thus continuing the use of their chosen contraceptive method - until the time when their bleeding becomes more regular or until they experience amenorrhea.
Description of the intervention
In the absence of complete understanding of the underlying mechanisms leading to vaginal bleeding irregularities, there are variations in clinical practice. In the early 1980s, a survey was conducted on the management of progestin-associated menstrual disturbances among physicians and organizations (Fraser 1983). There were 35 responses from 20 countries, most reporting experience with DMPA, and three with additional experience with NET-EN. Fourteen years later, another survey (Nutley 1997) was conducted among family planning providers and researchers on the treatment regimens they used for progestin-associated bleeding disturbances. Sixty four responses from 32 countries were received. The second survey collected information based on experience with injectable, implantable and oral progestin-only methods. Both surveys documented a wide variability of treatment regimens offered to women, ranging from estrogens, combined oral contraceptives, progestins, non-steroidal anti-inflammatory agents, to vitamins, iron and anxiolytic agents.
How the intervention might work
Because the exact etiology of vaginal bleeding irregularities associated/induced by progestin-only contraceptives is not completely elucidated, different interventions are targeting different possible mechanisms.For instance; estrogens may enhance those mechanisms that cause bleeding to cease, i.e. coagulation or tissue repair (Shaaban 1984 and Viegas 1988),the anti-progestin (mifepristone) may functionally inhibit progesterone, leading to up-regulation of endometrial estrogen receptors and a positive effect on bleeding patterns similar to exogenous estrogen treatment(Jain 2003), SERMs(tamoxifen) may improve bleeding patterns disrupted by the use of progestin-only contraceptives by antagonizing the angiogenic effect of estrogen (Grow 1998) and the antifibrinolytic agent(tranexamic acid) can reduce the amount of bleeding through slowing the process of dissolving the tiny clots that are formed as a result of bleeding (Lukes 2011).
Why it is important to do this review
This wide variation in treatments given to women, and the uncertainty about the potential benefits or risks of individual treatments, highlight the importance of conducting a rigorous and comprehensive review of the different treatments for vaginal bleeding irregularities associated with progestin-only contraceptives.
The purpose of this review is to evaluate prophylaxis and treatment of bleeding irregularities associated with the use of progestin-only contraceptives.
Criteria for considering studies for this review
Types of studies
Trials designed to test regimens to treat or prevent bleeding irregularities associated with the use of progestin-only contraceptive methods were considered for inclusion. Studies were required to use random or systematic (i.e. alternation) methods of allocation. Studies employing a cross-over design were not eligible for inclusion.
Types of participants
Women using progestin-only contraceptives were the participants of the studies included in this review. These comprise:
1. Women experiencing vaginal bleeding irregularities i.e. bleeding/spotting, irregular bleeding, prolonged bleeding, frequent bleeding or amenorrhoea. The trialists' definitions of these conditions were accepted.
2. Women not experiencing vaginal bleeding irregularities but accepting prophylactic treatment. These women would be likely to be enrolled as they start using the progestin-only contraceptive method.
Types of interventions
Drugs used to prevent or treat bleeding irregularities in women using progestin-only contraceptives. These are likely to include:
3. Combined oral contraceptives
4. Nonsteroidal anti-inflammatory drugs
6. Antifibrinolytic agents
7. Antiprogestins/progesterone receptor modulators
8. Selective estrogen receptor modulators
9. Antiangiogenesis agents
10 Matrix metalloproteinase inhibitors
12. Combinations of the above
The dose, duration and frequency of treatment and length of follow-up should be specified.
Types of outcome measures
The primary outcome of this review is the effectiveness of prophylactic or therapeutic interventions to prevent or treat bleeding irregularities, as defined by an improvement in irregular bleeding. Trials using objective or subjective methods for assessing bleeding were eligible.
Additional outcomes included:
1. Discontinuation of the contraceptive method
2. Discontinuation of the treatment
a. Discontinuation due to side-effects
b. Discontinuation due to lack of improvement
3. Any side-effect of treatment
4. Patient dissatisfaction with treatment
5. Blood loss during treatment
Outcome measures were assessed during treatment and/or at the end of treatment, to evaluate short-term effects, and at varying intervals following discontinuation of treatment, to evaluate long-term effectiveness, according to the study design.
Search methods for identification of studies
The search included:
1. ELECTRONIC DATABASES
a. MEDLINE using OVID or SilverPlatter for the years 1966-2006; searches were updated using Pubmed through May 2012.
b. EMBASE using OVID for the years 1980-2006; EMBASE through Elsevier for years 2006 – 2012.
The methodological search filter for high sensitivity in identifying randomised controlled trials in MEDLINE, parts I and II (11a.15 Appendix B, Cochrane Reviewers' Handbook 4.1, June 2000, p153) was added to the subject search strategy to identify reports of controlled trials in MEDLINE. This methodological search filter was adapted for use in searching EMBASE.
c. Popline was searched throughJune 7, 2012
d. The Cochrane Central Register of Controlled Trials (CENTRAL), which includes controlled trials identified from electronic databases as well as hand searching of relevant journals.
e. LILACS ( Literatura Latino Americana e do Caribe em Ciências da Saúde) which covers Latin American and Caribbean literature in Spanish, Portugese and English was searched with the same search terms.
The drug classes and individual names for progestin-only contraceptives, including their proprietary names used in different countries where known, were combined with terms describing vaginal bleeding irregularities in order to identify treatment interventions.
The following subject search terms were combined:
#1 explode PROGESTATIONAL-HORMONES-SYNTHETIC
#2 explode PROGESTERONE
#3 explode CONTRACEPTIVES-ORAL-SYNTHETIC
#7 progestogen only contracep* OR progestin only contracep*
#8 progesterone OR progestogen* OR norgestrienone OR norgestrel OR ogyline OR microlut OR microval OR mirena OR norplant OR levonova OR microluton OR follistrel OR neogest OR norgeston OR postinor-2 OR ovrette OR levonorgestrel OR norgestimate OR nomegestrol acetate OR norethisterone acetate OR norethisterone enanthate OR norethisterone enantate OR micronovum OR primolut-nor OR locilan OR micronor OR noriday OR norlutate OR milligynon OR norfor OR noristerat OR norluten OR gestakadin OR sovel OR conludag OR nur-isterate OR mini-pe OR menzol OR primolut-N OR sh420 OR utovlan OR aygestin OR nor-qd OR medroxyprogesterone acetate OR depo-provera OR depocon OR farlutal OR prodafem OR provera OR depo-ralovera OR ralovera OR depo-prodasone OR gestoral OR prodasone OR clinofem OR clinovir OR depo-clinovir OR g-farlutal OR lutoral OR perlutex OR petogen OR depo-progevera OR progevera OR cykrina OR gestapuran OR prodafem OR amen OR curretab OR cycrin OR lynoestrenol OR lynestrenol OR orgametril OR exluton OR exlutona OR exlutena OR gestodene OR etonogestrel OR implanon OR ethynodiol diacetate OR etynodiol diacetate OR lutometrodiol OR luteonorm OR femulen OR drospirenone OR desogestrel OR dienogest OR demegestone OR lutionex OR cyproterone acetate OR andro-diane OR androcur OR cyprone OR cyprostat OR chlormadinone acetate OR luteran OR gestafortin OR prostal OR algestone acetophenide OR neolution depositum OR levonorgestrel OR lng ius
#9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8
#10 explode UTERINE-HEMORRHAGE
#12 vagina* NEAR (bleed* OR haemorrhag* OR hemorrhag* OR blood loss)
#13 uter* NEAR (bleed* OR haemorrhag* OR hemorrhag* OR blood loss)
#15 (irregular OR prolonged OR frequent OR persistent OR unpredictable OR unscheduled OR abnormal OR breakthrough) NEAR (bleed* OR menstrual* OR menses OR blood loss OR period OR periods OR haemorrhag* OR hemorrhag*)
#16 menstrual disturbance*
#17 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16
#18 #9 AND #17
(N.B. Upper case denotes controlled vocabulary, which comprise Thesaurus terms applied by the database indexers, and lower case denotes free-text terms, which are used by the authors of the studies).
The search strategies of the different data bases are shown in Appendix A.
2. Reference lists of trials identified and relevant review articles were scrutinized for any additional trials not retrieved with the database searches listed above.
3. Researchers active in the field were contacted for possible unpublished studies or data.
The searches included all languages.
Data collection and analysis
Two reviewers (HAA and KV) initially assessed the results of the search by checking the titles and the abstracts where available. When unsure about the relevance or the methodology, they requested and reviewed full reports. Reports of studies using a random or quasi-random allocation and evaluating the interventions described here were critically appraised for inclusion.
A data extraction form was developed, as described in the Cochrane Handbook, for standardisation of the data extraction. Trials were reviewed for methodological quality based on concealment of allocation, outcome assessment blinding and drop out rates. If all of the criteria were met, there was considered to be a low risk of bias (validity criteria score A). In cases where one or more criteria were partly met, for example if the trialists reported that the study was double blind, but didn't report any concealment approach, there was considered to be a moderate risk of bias (validity criteria score B). If one or more of the criteria was not met, if allocation concealment or outcome assessment were not blinded, or if the study participant drop-out rate was more than 10%, studies were given a validity criteria score of C.
There were no language restrictions for inclusion of trials. Abstracted data were entered into Review Manager software and analysed. Studies that enrolled women who were using any levonorgestrel-releasing subcutaneous implant (either the 2-rod Jadelle system or the 6-rod Norplant system) were combined, since these methods release the same hormone at the same daily rate. Otherwise, studies that enrolled women who were using different contraceptive methods were not combined, due to the different primary mechanisms of contraceptive action of the various methods, and their differing effects on bleeding patterns. Since the types and mechanisms of pharmaceutical agents used were different and the desired outcomes of treatment differed between trials (for example induction of regular menses or of amenorrhoea), different groups of agents were not combined in a single analysis. Therefore, three main variables were identified in the comparison plan: the contraceptive method, the intervention, and the prophylactic or therapeutic nature of the intervention. Few trials could be combined and we conducted the analyses with this consideration in mind.
Data regarding participant drop out rates, loss to follow up and reasons for early discontinuations were recorded and presented in the table of included studies. Study participant characteristics, treatment interventions, length of follow-up and outcome measures were recorded. Trial characteristics such as type of trial, study duration and setting where the trials were conducted were also recorded.
The data were extracted separately by two reviewers (HAA and KV) and discrepancies or disagreements were resolved by discussion and consultation with a third reviewer (MEG). Data were entered for analysis by KV and MEG. The results are expressed as relative risks (RR) with 95% confidence interval (CI) in case of categorical data and as weighted mean difference (WMD) with 95% confidence interval (CI) for continuous data, using a fixed-effect approach where possible. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative).
Description of studies
This review included 33 randomised (n=32) or systematically allocated (n=1) controlled trials (RCTs), conducted in 17 countries (China, Indonesia, Iran, Pakistan, the Philippines and Thailand in Asia; Tunisia and Egypt in Africa; France, the Netherlands, Sweden, Switzerland and the United Kingdom in Europe; the United States of America in North America; Chile and the Dominican Republic in Latin America; and Australia). Studies were conducted at family planning clinics, hospitals and university research centres.
Twelve of the included studies enrolled women using Norplant as their contraceptive method. New Norplant users, as well as women using the method for one to 43 months were enrolled; most of the studies limited enrolment to women using the method for less than one year. Twelve studies were conducted to evaluate interventions in women using the injectable DMPA. Two of these enrolled new users, with the aim of evaluating interventions to prevent bleeding irregularities; the remaining studies enrolled women who had been using the method for one to 18 months. In three trials, women used progestin-only pills; the duration of use was at least one month in one study and was not defined in the other two studies. Three trials recruited women who had been using Implanon for a period of more than two months. Two studies enrolled new users of the Mirena LNG-IUS. One study was conducted to evaluate treatment of irregular bleeding in Jadelle users.
Characteristics of participants:
The age of women included in these trials generally was in the range of 20 to 30 years; however, many of the studies' inclusion criteria allowed for the enrolment of women up to age 45.. Two studies (Subakir 2000, and Weisberg 2006) included women 18 to 40 years old. One study (Harel 2002) specifically enrolled adolescent girls; the mean age of participants in this trial was 16 ± 1 years. The parity of women recruited in the trials was reported in only 13 trials and ranged between zero and five. The body weight of study participants was reported in 11 trials and mean body weights were reported in the range between 44 and 73 kg. Height was not mentioned in the majority of the trials, but nine studies reported the body mass index; in these trials BMI ranged from 21 to > 30 kg/m2.
There were 18 types of interventions tested in the trials. Fourteen interventions were tested as therapeutic treatments. These included estrogens alone in various formulations (ethinyl estradiol,17-beta estradiol, diethylstilbestrol, oestrone sulphate, quinesterol), as used in seven trials (Alvarez-Sanchez 1996, Archer 2008, Boonkasemsanti 1996, Diaz 1990, Johannisson 1982, Said 1996 and Witjaksono 1996). Estrogen - progestin combinations were used therapeutically in three trials (Alvarez-Sanchez 1996, Sadeghi-Bazargani 2006 and Witjaksono 1996). A progestin was used therapeutically in a single trial (Diaz 1990). Anti-progestins were used therapeutically in two trials (Cheng 2000 and Weisberg 2006). An antiprogestin was combined with an estrogen as a method to treat irregular bleeding in two trials (Weisberg 2006, Weisberg 2009). A capillary protecting venotonic drug (registered in France as Cyclo 3, containing extract of Ruscus aculeatus with ascorbic acid and hesperidin methyl chalcone) was used therapeutically in one trial (Monteil-Seurin 1985). In two trials (Subakir 2000 and d'Arcangues 2004), vitamin E was used therapeutically. Non-steroidal anti-inflammatory drugs (NSAIDs) were used therapeutically in eight trials (Archer 2008, Buasang 2009, Diaz 1990, Kaewrudee 1999, d'Arcangues 2004, Nathirojanakun 2006, Phaliwong 2004 and Tantiwattanakul 2004). The therapeutic effects of combined Vitamin E and NSAIDs were evaluated in a single trial (d'Arcangues 2004). A selective estrogen receptor modulator (SERM) was used therapeutically in one trial (Abdel-Aleem 2005). An antifibrinolytic agent was used in two trials (Phupong 2006, Senthong 2009). A matrix metalloproteinase inhibitor (MMPI) alone was used in three trials (Abdel-Aleem 2012, Weisberg 2006, Weisberg 2009). One trial evaluated the effects of combined MMPI and estrogen treatment ( Weisberg 2009); this same study also evaluated MMPI combined with an antiprogestin.
Four types of interventions were tested for their effects to prevent bleeding irregularities in users of progestin-only contraceptives. These included estrogens alone (estradiol acetate, diethylstilbestrol, 17-beta estradiol, quinesterol) as used prophylactically in five trials (Dempsey 2010, El-Habashy 1970, Goldberg 2002; Madden 2012 and Parker 1980). Anti-progestins were used prophylactically in four trials (Gemzell-Danielsson 2002 , Jain 2003, and Massai 2004 and Warner 2010). The effects of vitamin C in preventing bleeding irregularities in new DMPA users were evaluated in a single four-arm trial (Harel 2002). In addition, a trial of new LNG-IUS users provided an NSAID for prophylaxis (Madden 2012).
All trials except (Dempsey 2010) were placebo-controlled. Twenty four trials included a single intervention arm, while nine trials were designed to test the effects of more than one intervention, singly or in combination. In two trials (El-Habashy 1970 and Parker 1980) the interventions tested, diethylstilbestrol and quinesterol, respectively, are no longer used in clinical practice, for any indication. In addition to the range of types of interventions, the treatments were used in different doses and according to different dosing schedules, and study participants were followed according to diverse schedules, for varying lengths of time.
Duration of Follow-Up:
The duration of follow-up varied among the trials, from less than three months to eighteen months. Most trials were designed to test the short-term effects of the interventions, with only eight trials treating or following participants for longer than six months (Archer 2008, Parker 1980, Diaz 1990, Said 1996, Cheng 2000, Goldberg 2002, Massai 2004 and d'Arcangues 2004). The longest duration of follow-up, as reported in two studies (Archer 2008, Said 1996) was one year and up to 18 months, respectively ; however, the long-term results were not reported.
Although nearly all trials were designed to evaluate the effects of treatment on bleeding episodes as a primary outcome, the authors reported the outcome in different ways, including cessation of bleeding, number of bleeding days during treatment, number of bleeding days after treatment, number of days of treatment required before bleeding stopped, percent of women with bleeding free intervals of more than a given number of days, percent of women with acceptable bleeding, and others. Moreover, the data were presented in different ways including means, medians, and percentages. Other types of outcome measures included discontinuation of the treatment, discontinuation of the contraceptive method, side effects due to treatment, dissatisfaction with treatment and, in a few studies, blood loss during treatment.
Due to the lack of consistency in study design, outcome measures, and statistical reporting, very few studies could be combined in the analyses.
Risk of bias in included studies
This review included 33 trials. The methodological quality was assessed as mentioned above, in the methods section, with validity criteria scores based on allocation concealment, outcome assessment blinding and number/percent of study discontinuations. The overall assessment of risk of bias is shown in (Figure 1). According to these criteria, 10 of the trials were assigned "A" validity criteria scores with low risk of bias ( Abdel-Aleem 2005,Archer 2008, Buasang 2009, Cheng 2000, Kaewrudee 1999, Nathirojanakun 2006, Phaliwong 2004, Phupong 2006, Senthong 2009 and Weisberg 2006). In these trials, allocation concealment was considered to be adequate, outcome assessment blinding was achieved and fewer than 10% of the enrolled women discontinued prior to the end of the study(Figure 2). There were 12 trials that were considered to be at moderate risk of bias and were therefore given validity criteria scores of "B". In many of these studies, the allocation concealment was unclear ( Boonkasemsanti 1996, Jain 2003, Johannisson 1982, Massai 2004, Subakir 2000). The outcome assessment blinding was unclear or inadequate in three of these trials ( El-Habashy 1970, Jain 2003, Johannisson 1982 ).In two trials the drop out rate was >10% but less than 15%(Abdel-Aleem 2012,Weisberg 2009). Eleven trials were given a validity criteria score of "C", meaning that the study may be subject to a high risk of bias (Alvarez-Sanchez 1996, d'Arcangues 2004, Dempsey 2010,Gemzell-Danielsson 2002, Diaz 1990, Goldberg 2002,Madden 2012, Monteil-Seurin 1985, Parker 1980, Said 1996 and Witjaksono 1996).In all these trials at least two of the criteria were unmet or not clear or the drop out rate was markedly high. Overall, two thirds of the trials were of high to moderate quality , with 34% being considered "poor." The 10 trials (30% of all included studies) that were considered to be of good quality recruited 855 (23%) of 3,677 women enrolled in all included trials.
|Figure 1. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
Effects of interventions
1. Estrogen versus placebo (therapeutic treatment for LNG subcutaneous implant users; n=5 studies)
In five of the included studies, women reporting bleeding irregularities while using Norplant were administered an estrogen formulation and followed for resolution of symptoms (Alvarez-Sanchez 1996, Archer 2008, Boonkasemsanti 1996, Diaz 1990, and Witjaksono 1996). Together, these studies recruited 166 women in the respective estrogen treatment arms and 185 women in placebo groups; of these, data from 147 estrogen-treated women and 173 placebo-treated women were included in the analyses. Treatments included ethinyl estradiol (EE) tablets in four studies (Alvarez-Sanchez 1996, Archer 2008, Diaz 1990 and Witjaksono 1996) and an estradiol patch in the fifth (Boonkasemsanti 1996).
The efficacy of the various treatments was reported in different manners in these studies. In Alvarez-Sanchez 1996, the primary outcomes included whether or not bleeding stopped within three days of the initiation of treatment and the number of bleeding days during the 20-day treatment interval. Archer et al (Archer 2008) reported the main study outcomes as being the mean duration (number of days) of bleeding and/or spotting during various intervals throughout the one-month follow up period; however, the effect of EE treatment was inestimable, since standard deviations were not published. The Diaz 1990 study reported mean and total numbers of bleeding and spotting days during all treatment intervals throughout the entire year and did not separate individual treatment intervals. Women receiving estradiol reported shorter episodes of bleeding and spotting throughout the year and fewer days of bleeding and spotting. However, it is not clear how many treatment cycles were included in the analysis. But it is reported that the mean number of treatments per year per treated subject ranged from 2.2 to 3.1, with no differences between groups. Witjaksono 1996 reported on the number of bleeding or spotting days and episodes in 90-day reference periods prior to and following the treatment, and the number of bleeding or spotting days per episode. The study results from the individual trials generally suggest that the estrogen treatment had a beneficial effect in stopping bleeding. Two of the included studies (Alvarez-Sanchez 1996 and Boonkasemsanti 1996) reported the number of women who experienced irregular bleeding during treatment; according to our combined analysis, the use of estrogen reduced irregular bleeding during the treatment interval [RR 0.43, 95% CI 0.30-0.61 ). In addition, the Alvarez-Sanchez 1996 data support the conclusion that women receiving EE report a lower incidence of unacceptable bleeding patterns after treatment, as defined by the length of the post-treatment bleeding-free interval. Fewer women reported a bleeding-free interval of less than 11 days after receiving the oral EE regimen than after receiving placebo [RR 0.28, 95% CI 0.14 ,0.58]. In contrast, no differences in the number of bleeding and/or spotting days within the 20 days following a 10-day EE treatment period were reported by Archer et al (Archer 2008).
Based on our analysis of data reported by Alvarez-Sanchez 1996, women receiving estrogen treatment appeared to be less likely to discontinue the use of Norplant for bleeding irregularities than were those receiving placebo, though the overall effect was not significant, as only one woman discontinued for this reason. Diaz 1990 did not report any method discontinuations for bleeding irregularities. Nausea or gastrointestinal discomfort was commonly reported in the former study: only two of 46 participants receiving placebo reported such side effects, whereas 17 of 43 receiving estrogen complained of gastric upset [RR 9.09, 95% CI 2.23, 37.06]. In the Diaz 1990 study, 5 of 13 study discontinuations in the estrogen group were associated with gastric intolerance, while none of the women in the placebo group discontinued from the study for this reason. Alvarez-Sanchez 1996 reported discontinuation of treatment due to gastralgia or nausea in 2 of 50 women receiving treatment and none of the women in the placebo group. When the data for these studies were combined, it was clear that women receiving estrogen tended to be more likely to discontinue their participation in the trial due to side effects of the treatment than were women receiving placebo [RR 8.1, 95% CI 1.04, 63.40].
2. Estrogen versus placebo (therapeutic treatment for DMPA users; n= 1 study)
Only one of the included studies (Said 1996) was designed to evaluate the effects of an estrogen on bleeding irregularities in women using DMPA for family planning. This was one of the largest included studies, having randomised 278 DMPA users with irregular bleeding to receive either EE 50 µg, oestrone sulfate 2.5 mg or placebo for 14 days. This study was also designed to report on both short- and long-term success, with follow-up at 14 days (the duration of the treatment) and 12-18 months; unfortunately, there was a high rate of discontinuation (over 40% in each group), giving the study a high risk of bias.
Ethinyl Estradiol was effective in stopping bleeding during treatment [RR 0.26, 95%CI 0.11, 0.60] and to a lesser extent after three months [RR 0.06, 95%CI 0.00, 1.00] . Oestrone sulphate was ineffective in stopping bleeding during treatment [RR 1.03, 95%CI 0.41, 2.59] and after three months.
The authors reported discontinuations and their causes among the study participants who presented at the study centres. But due to the high numbers of study participants who were lost to follow-up and who dropped out of the study prematurely, without giving a reason, it was impossible to determine the true discontinuation rates, particularly as related to bleeding irregularities and side effects, respectively.
3. Estrogen versus placebo (prophylactic treatment for DMPA users; n= 4 studies)
Four studies were identified in which estrogen was administered to new acceptors of DMPA, with the goal of preventing or reducing bleeding irregularities. Two of these (El-Habashy 1970 and Parker 1980) examined the effects of orally administered estrogens, diethylstilbestrol (DES) and quinesterol, respectively, the third (Goldberg 2002) evaluated the effects of a 17-beta estradiol-containing transdermal patch and the most recent study evaluated the use of a vaginal ring releasing estradiol acetate (Dempsey 2010).
Two of the studies reported efficacy of the treatment in terms that could be incorporated into the present analysis. El-Habashy 1970 reported that women administered DES 1 mg daily exhibited more acceptable bleeding patterns (defined as bleeding episodes of less than 8 days) than women receiving placebo [RR 0.45, 95% CI 0.21, 0.96]. The trial of the vaginal ring (Dempsey 2010) reported that the mean number of days of bleeding during treatment was reduced in women using the ring; however this finding was not statistically significant, with a weighted mean difference of -8.30 days in the treatment group (95% CI -20.2, 3.6). Parker 1980 reported the percent of women with acceptable bleeding patterns in terms of numbers of bleeding episodes throughout 3-month intervals, following either one or three doses of quinestrol per DMPA injection segment (12 weeks). The primary outcome of the (Goldberg 2002) study was DMPA continuation rates and (Dempsey 2010 also reported on this outcome. The combined analysis demonstrated that estrogen treatment is ineffective as a means to improve DMPA continuation [RR 1.00, 95% CI 0.78, 1.28]. Three of the studies in this category suffered from very high discontinuation and non-compliance rates, in both treatment and placebo groups
4. Estrogen versus placebo (therapeutic treatment for minipill users; n= 1 study)
One small (n=12) study (Johannisson 1982) was designed to evaluate the effects of estrogen treatment on bleeding irregularities experienced by minipill (300 µg norethisterone) users. The bleeding data could not be used in the current analysis, as confidence intervals, rather than standard deviations, were presented in the descriptions of bleeding during the treatment interval.
5. Combined estrogen and progestin versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 2 studies)
There were two studies (Alvarez-Sanchez 1996; Witjaksono 1996) in which a combination of oral ethinyl estradiol and oral levonorgestrel was tested as a means to treat bleeding irregularities in Norplant users. The two studies together randomised 66 women to receive the treatment regimen and 64 to receive placebo; of these 61 and 60, respectively, were included in the analyses. As above, Alvarez-Sanchez 1996 reported efficacy in terms of the percentage of women who experienced a cessation of bleeding within 3 days of treatment; the Witjaksono 1996 paper reported the number of bleeding days and episodes in 90-day reference periods. According to the reports of the author and to our analyses, in the former study, the combined approach significantly reduced continued irregular bleeding during treatment, when compared with placebo [RR 0.08, 95% CI 0.03, 0.24] and reduced unacceptable bleeding after treatment (as defined by the number of women experiencing bleed-free intervals of less than 11 days) [RR 0.02, 95% CI 0.00, 0.29].
Witjaksono 1996 did not report discontinuations or side effects in the study results; (Alvarez-Sanchez 1996) reported that the discontinuation of Norplant due to bleeding disturbances was not significantly different between women in the combined hormone treatment and placebo groups, which was supported by our analysis [RR 0.33, 95% CI 0.01, 7.99]. Discontinuation due to the side effects of the treatment did not differ between groups; however, our analysis of the Alvarez-Sanchez data revealed a higher incidence of reported side effects (nausea or gastralgia) in the treatment group than in the placebo group [RR 7.16, 95% CI 1.72, 29.71].
6. Combined estrogen and progestin versus placebo (therapeutic treatment for DMPA users; n= 1 study)
One small trial (Sadeghi-Bazargani 2006 ) recruited DMPA users who had cessation of menstruation for two months. Twenty four women received low dose combined oral contraceptives (COCs) and 22 received placebo. Significantly fewer women in the treatment group than in the placebo group continued to experience amenorrhea [RR 0.38, 95% CI 0.19, 0.73]. The number of women who discontinued use of DMPA was less in the group assigned to receive low dose pills [RR 0.60, 95% CI 0.40, 0.88].
7. Progestin versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 1 study)
One study (Diaz 1990) evaluated the effect of administering an additional progestin to Norplant users experiencing bleeding episodes of eight or more days. These women received 0.03 mg levonorgestrel tablets, twice a day for 20 days, starting on the eighth consecutive day of bleeding. Women could treat extended bleeding up to five times in the year-long study. The authors described a significant decrease in the total number of bleeding days and bleeding and spotting days over the entire year in women who ever used the levonorgestrel, compared with those who ever used the placebo, even when the untreated bleeding cycles were included in the analysis; however, the numbers of women in the final analysis were small (21 per group).
Three of the 47 women enrolled in the levonorgestrel group elected to have their Norplant system removed, though none for reasons related to bleeding; only one woman in the placebo group asked to discontinue the contraceptive method [RR 2.94, 95% CI 0.32, 27.21].
8. Antiprogestin versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 1 study)
One of the included studies (Cheng 2000) was designed to evaluate the effects of the anti-progestin mifepristone on bleeding irregularities experienced by users of levonorgestrel-containing subdermal contraceptive implants equivalent to Norplant. The study results stated that the women treated with mifepristone reported significantly shorter episodes of bleeding during the treatment than prior to the study; however, both the treatment and control groups demonstrated a decrease in the frequency of bleeding in the one year of follow up. In the current analysis, we found no significant difference between the groups with respect to the number of days of bleeding during treatment when reported 3 months after study initiation; at 6 months, however, women using the anti-progestin reported fewer days of bleeding than did those receiving placebo [WMD -8.00, 95% CI -12.41, -3.59]. No difference in the number of days of bleeding after the treatment was noted. No women in either group discontinued the use of the contraceptive method due to bleeding irregularities. There was a significant effect of mifepristone to decrease patient dissatisfaction with the treatment [RR 0.46; 95% CI 0.23, 0.91].
9. Antiprogestin versus placebo (prophylactic treatment for LNG subcutaneous implant users; n= 1 study)
A single study (Massai 2004) was designed to evaluate the effect of two subsequent daily oral doses of 100 mg mifepristone in preventing bleeding irregularities in new users of Norplant. Of the 120 women enrolled, 116 completed 6 months of treatment and 115 were included in the analysis. The mean number of bleeding or spotting days during the course of the 180 days of the treatment period of the trial was significantly lower in women who had taken mifepristone for 2 days at 30 day intervals than in women given placebo [WMD -18.0; 95% CI -26.93, -9.07]. However, the improvement in bleeding patterns did not continue past the time of discontinuation of treatment and, by 6 months after treatment, there were no differences in reported acceptable bleeding patterns between the two groups. None of the women in the treatment group discontinued use of Norplant for continued irregular bleeding. Of importance, one woman who received the anti-progestin did become pregnant during the course of the study. Two women in the placebo group elected to have their implants removed due to continued irregular bleeding. This difference was not found to be significant, nor was the difference between groups with respect to discontinuation from the study due to side effects of the treatments, in the current analysis.
10. Antiprogestin versus placebo (therapeutic treatment for Implanon users; n=1 study)
One pilot study (Weisberg 2006) randomised women who used Implanon implant and had bleeding irregularities to receive mifepristone (25 mg twice/day for one day) then placebo for four days or placebo only for five days. The authors reported that mifepristone alone was similar to placebo in stopping an episode of bleeding. Unfortunately, the results were presented in a way not suitable for our analysis. A similar proportion of women in both groups reported any side effect [0.93, 95% CI 0.61, 1.42] or, specifically, nausea and vomiting [0.64, 95% CI 0.23, 1.80].
11. Antiprogestin versus placebo (prophylactic treatment for DMPA users; n= 1 study)
Results of one small study (Jain 2003) suggest that a single tablet of 50 mg mifepristone, taken orally every 14 days, can lessen bleeding irregularities in new users of DMPA, in terms of percent days with breakthrough bleeding and percent cycles with bleeding intervals of more than 8 days.
12. Antiprogestin versus placebo (prophylactic treatment for minipill users; n= 1 study)
In one study (Gemzell-Danielsson 2002), 103 women were randomised to take either 150 mg of a novel antiprogestogen (Org 31710) or placebo tablets once every 28 days, for a maximum of seven treatment cycles. Although the study authors report an improvement in the bleeding patterns of women who received the antiprogestin, our analysis did not reveal any differences between groups in terms of efficacy, discontinuation of the contraceptive method due to bleeding irregularities or side effects, or the incidence of side effects or adverse events.
13. Combined antiprogestin and estrogen versus placebo (therapeutic treatment for Implanon users; n= 1 study)
One pilot study (Weisberg 2006) and a larger follow-on trial (Weisberg 2009) randomised women using Implanon and experiencing bleeding irregularities to take either mifepristone 50 mg for one day, followed by EE 20 µg/day for four days, or placebo for five days. The efficacy results were presented in a way not suitable for our analysis but the authors reported in both trials that mifepristone followed by EE was significantly more effective than placebo in stopping an episode of bleeding. Data extracted from the more recent trialWeisberg 2009 reflect the number of women who experienced continued irregular bleeding during treatment; none of the 40 women randomized to receive the active treatment reported continued bleeding, compared with 11 of the 37 women who received placebo [RR 0.04, 95% CI 0.00, 0.66]. The analysis of the pilot study demonstrated no significant differences between the two groups of women in reporting any side effects [RR 1.22, 95% CI 0.84, 1.75]. The 2009 trial reported no difference between treatment groups with respect to the number of women who experienced headache; a combined analysis of both trials revealed no effect of treatment group on the number of women experiencing nausea or vomiting [RR 0.5, 95% CI 0.18, 1.38]. The more recent trial reported on discontinuation of the contraceptive method at 90 and 180 days following initiation of treatment. Treatment with mifepristone followed by EE did not result in a favourable effect on method continuation rates at either time point.
14. Venotonic versus placebo (therapeutic treatment for minipill users; n= 1 study)
In one of the included studies (Monteil-Seurin 1985), women using a norethisterone acetate-containing minipill and complaining of bleeding irregularities were administered either a capillary protecting venotonic drug (registered in France as Cyclo 3, containing extract of Ruscus aculeatus with ascorbic acid and hesperidin methyl chalcone) or placebo. The treatment schedule was cyclic, with drug exposure for 20 continuous days, followed by a drug-free period during the expected time of menses. The mean number of bleeding days during treatment was lower in the group using the venotonic drug in comparison to the placebo group [WMD -2.0, CI -2.78, -1.22]. This was the only one of the included studies that attempted to quantify the amount of blood lost during treatment, as a listed endpoint, and the study authors indicated that women who received the Cyclo 3 needed less menstrual protection than did women in the placebo group. There were no study drop outs reported and no data were presented on side effects due to the treatment. According to the study authors, treated women subjectively reported less discomfort due to bleeding after 3 treatment cycles than did women who received placebo.
15. Vitamin E versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 2 studies)
Two of the included studies (d'Arcangues 2004 and Subakir 2000) were conducted to evaluate the effectiveness of vitamin E, 200 mg/day for 10 days, in the treatment of bleeding irregularities experienced by women using Norplant implants. In Subakir study, the mean number of bleeding days after the first treatment cycle was significantly less among the 38 women taking vitamin E than among the 34 women assigned to the placebo group [WMD -4.4, CI -5.02, -3.78]. However, in the second, larger study (d'Arcangues 2004), with more than 100 women in each group, there were no statistically significant differences between the groups in terms of the length of bleeding/spotting episodes and the length of bleeding-free intervals that followed cessation of bleeding. d'Arcangues 2004 reported median numbers of days of bleeding, rather than means, given the non-normal distribution of the data. In this study, discontinuation rates were high but did not differ between groups, nor did the incidence of side effects.
16. Non-steroidal anti-inflammatory drug versus placebo (therapeutic treatment for LNG subcutaneous implant users; n=5 studies)
Five of the included studies (Archer 2008, Buasang 2009, d'Arcangues 2004, Diaz 1990 and Kaewrudee 1999) were designed to evaluate the effects of non-steroidal anti-inflammatory drugs (NSAIDS) on bleeding irregularities experienced by women using LNG-releasing sub-cutaneous implants (either Norplant or Jadelle). The regimens included oral ibuprofen 800 mg, three times/day for five days (Diaz 1990); oral ibuprofen 800 mg, two times/day for five days (Archer 2008); oral mefenamic acid 500 mg, twice daily for 5 days (Kaewrudee 1999); and oral aspirin, 80 mg/day for 10 days (d'Arcangues 2004) and celecoxib 200 mg/day for five days (Buasang 2009).
The earliest paper reported that women taking ibuprofen experienced a decrease in the mean number of bleeding days after initiating treatment in all treated bleeding intervals over the course of a year and fewer bleeding and spotting days during the year (Diaz 1990). Of data from Kaewrudee and Buasang , 14 of the 54 women taking an NSAID continued to experience irregular bleeding during the treatment, compared with 44 of 53 women in the placebo group [RR 0.32; 95% CI 0.2, 0.51]. In addition, Kaewrudee et al reported that women randomized to the mefenamic acid group experienced fewer days of bleeding during the treatment [WMD -5.6; 95% CI -10.04, -1.16]. The percentage of women with unacceptable bleeding after treatment was significantly less in the treated group as reported by both( Kaewrudee 1999 and Buasang 2009 )and confirmed in the present combined analysis [RR 0.38; 95% CI 0.25, 0.6]. In the d'Arcangues 2004 trial, the median duration of bleeding/spotting episodes after treatment and the median lengths of the bleed-free intervals were not significantly different in the drug and placebo groups, as reported by the authors. Archer et al (Archer 2008) reported the main study outcomes as being the mean duration (number of days) of bleeding and/or spotting during various intervals throughout the one-month follow up period; however, the effect of ibuprofen treatment was inestimable, since standard deviations were not published. No differences in the number of bleeding and/or spotting days within the 25 days following a five-day ibuprofen treatment period were reported by these authors.
In the Diaz 1990 trial none of the women receiving ibuprofen requested removal of the Norplant system, while one woman in the placebo group requested removal, though not for bleeding-associated reasons. No differences in discontinuation rates or incidence of side effects (headache and gastrointestinal upset) were noted in the single studies or in the combined analyses (where combinations were feasible). Patient dissatisfaction with treatment was significantly lower as reported by Jadelle users taking celecoxib for bleeding irregularities, in comparison with the placebo group (Buasang 2009) [RR 0.29; 95% CI 0.11, 0.72].
17. Combined non-steroidal anti-inflammatory drug and vitamin E versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 1 study)
In the large study reported in d'Arcangues 2004, over 120 women using Norplant were randomly assigned to receive a combination of aspirin and vitamin E, while the same number received placebo. The efficacy data were reported as medians, and no benefit of the treatment was demonstrated in the original analysis. In addition, our analyses indicated that there were no differences between the groups with respect to study discontinuation or side effects related to the treatment .
18. Non-steroidal anti-inflammatory drugs versus placebo (therapeutic treatment for DMPA users; n= 2 studies)
Two trials (Tantiwattanakul 2004 and Nathirojanakun 2006) evaluating the therapeutic effect of an NSAID on bleeding patterns in women using DMPA were included in the analysis. In the first, women were randomised to receive mefenamic acid (n=23) or placebo (n=25). In the second trial, 46 women were randomised to receive either valdecoxib or placebo. . In a combined analysis, fewer women receiving NSAID treatment continued bleeding during or just after the treatment period, versus in the placebo group [RR 0.42; 95% CI 0.25, 0.72]. In the first trial gastrointestinal discomfort was reported by six women in the treatment group and by none in the control group; this difference was not found to be significant in our analysis. In the second trial no adverse effects were reported.
19. Selective estrogen receptor modulator versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 1 study)
Abdel-Aleem 2005 was the only included trial to examine the efficacy of a selective estrogen receptor modulator (SERM), in this case tamoxifen, on bleeding irregularities experienced by women using progestin-only methods of fertility regulation. The study was limited to women using Norplant. women received tamoxifen, 10 mg tablets twice daily for 10 days or placebo. Women randomised to the treatment arm were significantly less likely to experience irregular bleeding during treatment [RR 0.41; 95% CI 0.21, 0.80] or unacceptable bleeding after treatment [RR 0.38; 95% CI 0.18, 0.88] or to discontinue the use of Norplant for any reason [RR 0.20; 95% CI 0.05, 0.87]. The effect of the SERM in reducing Norplant discontinuation for bleeding-related reasons bordered on significance [RR 0.22; 95% CI 0.05, 0.98]. Women receiving tamoxifen were more likely to report satisfaction with their treatment regimen [RR 0.22; 95% CI 0.11, 0.45] and were no more likely to report side effects.
20. Antifibrinolytic versus placebo (therapeutic treatment for LNG subcutaneous implant users; n= 1 study)
One randomised trial (Phupong 2006) evaluated the effects of an antifibrinolytic agent on bleeding patterns in women using Norplant and reporting irregular bleeding. Sixty-eight Norplant users were enrolled; half received tranexamic acid 500 mg twice/day for five days and the other half received similar placebo. The percentage of women whose irregular bleeding stopped at 7 days after the initiation of treatment was significantly higher in the tranexamic acid group than the placebo group [RR 0.55, 95 % CI 0.32, 0.92]. The percentage of women with unacceptable bleeding by four weeks after the initiation of treatment was higher in the treatment group (41%) than in the control group (24%) [RR 1.75, 95% CI 0.85, 3.62].
21. Matrix metalloproteinase inhibitor versus placebo (therapeutic treatment for Implanon users; n= 2 studies)
In a pilot study (Weisberg 2006) and a larger follow-on trial (Weisberg 2009), Implanon users who experienced prolonged or frequent bleeding patterns were randomised to receive doxycycline 100 mg/twice daily or similar placebo, for five days. Follow up was for a period of 90 days in the pilot study; the larger trial implemented a 90-day treatment period, then a 90 day follow-up period. In the earlier study, the authors reported that doxycycline was more effective than placebo in stopping an episode of bleeding; this finding was not replicated in the larger trial. Data extracted from the 2009 trial showed no treatment benefit with respect to continued irregular bleeding during treatment; 11 of the 32 women randomized to receive the active treatment reported continued bleeding, compared with 11 of the 37 women who received placebo [RR 1.16, 95% CI 0.58, 2.3].
At 90 and 180 days following initiation of treatment, there were no differences in Implanon discontinuation rates between women receiving doxycycline and those receiving placebo [RR 0.98; 95% CI 0.26, 3.64] and [RR 0.76; 95% CI 0.31, 1.84], respectively.
There were no differences in the reporting of any side effects between the two groups [RR 0.83, 95% CI 0.53, 1.29]. The side effect of nausea/vomiting was reported in both trials; a combined analysis demonstrated no benefit of the treatment, though results were inconsistent between the studies. In the 2009 trial, fewer women reported headache in the treatment group; however, this finding was not significant.The authors reported that there was good compliance with treatment intake, with only 10% of study participants reporting having missed any tablet.
22. Matrix metalloproteinase inhibitor versus placebo (therapeutic treatment for DMPA users; n=1 study)
In a recently published trial (Abdel-Aleem 2012), 68 women using DMPA who experienced prolonged or frequent bleeding and/or spotting patterns were randomised to receive doxycycline 100 mg/twice daily or an identical placebo, for five days. Trial participants were followed for three months after the initial treatment to compare patterns of bleeding and spotting. When compared with a placebo, doxycycline treatment showed no benefit in stopping an episode of bleeding within 10 days of treatment (RR 0.88, 95% CI 0.64, 1.21). Moreover, during the follow-up of two cycles post treatment, no differences in either the mean number of bleeding or spotting days recorded by study participants were observed. Two women in doxycycline arm (2/34) and three women taking placebo (3/34) discontinued using DMPA during the trial (RR 0.67, 95% CI 0.12, 3.74). Several women reported side effects due to their treatments: in the doxycycline arm, two women experienced nausea and one complained of diarrhoea; whereas one woman who received placebo reported nausea.
23. Antifibrinolytic versus placebo (therapeutic treatment for DMPA users; n= 1 study)
One randomized trial (Senthong 2009) evaluated the effects of tranexamic acid for treatment of irregular bleeding secondary to use of DMPA. One hundred women were enrolled and randomized to receive either tranexamic acid (1000 mg per day for five days) or placebo, and were followed for four weeks after the initial treatment. Current analysis of the study results showed that six out of the 50 women who were assigned the treatment group, and 45 of the 49 women in the placebo group, experienced continued irregular bleeding during the first week of treatment [RR 0.13, 95% CI 0.06, 0.28]. There was also a significant effect of tranexamic acid on unacceptable bleeding after treatment; women in the treatment group experienced fewer days of bleeding and spotting in the four week follow-up period [mean number of days: 5.7 ± 2.5 days vs 17.5 ± 7.2 days, respectively].
24. Non-steroidal anti-inflammatory drug versus placebo (therapeutic treatment for Implanon users; n= 1 study)
A single trial (Phaliwong 2004) evaluated the effects of mefenamic acid for treatment of irregular bleeding secondary to use of Implanon. Fifty women were enrolled and randomized to receive either 1500 mg mefenamic acid per day for five days or placebo. They were followed for four weeks after the initial treatment. Eight out of 23 women who were assigned to the treatment group, and 18 of the 23 women in the placebo group, experienced continued irregular bleeding during the first week following initiation of treatment [RR 0.44, 95% CI 0.24, 0.81, current analysis]. Duration of bleeding and spotting during the 28 days of follow-up was reported by the authors to be significantly less among women taking mefenamic acid compared with women assigned to the placebo group [mean number of days: 10.5 days vs 16.8 days, respectively]; however, we were unable to estimate the mean difference in continued irregular bleeding because the standard deviations were not published.
Due to the small number of women enrolled in the trial, and wide confidence intervals surrounding the point estimate of effect, in the current analysis of the results, there were no observed differences in side effects experienced by women taking mefenamic acid compared with placebo. Abdominal discomfort was reported by three women in the treatment group, compared with none in the placebo group. Headache was reported by one woman in each group and breast tenderness was experienced by two women in the mefenamic acid group, but none in the placebo group.
25. Antiprogestin versus placebo (prophylactic treatment for LNG IUS users; n= 1 study)
One randomized trial (Warner 2010) evaluated the prophylactic effect of the use of an antiprogestin to reduce bleeding irregularities among new users of the LNG IUS. 136 women were enrolled; 69 were randomized to receive CDB-2914 (150 mg per day for three days, starting on days 21, 49 and 77 after device insertion) and 67 received placebo. Follow up visits were scheduled at 1, 3 and 6 months after device insertion. According to current analysis,during the first 28 days following the initial treatment (i.e. initiation on day 21 following LNG IUS insertion), there was a significant difference in the percentage of days in which women experienced bleeding and/or spotting. Women taking anti-progestins reported, on average, bleeding and/or spotting on 46.7% ± 20.6 days during the 28 day period, whereas women in the placebo group recorded irregular bleeding on 57.3% ± 24.8 days during the first 28-day cycle. However, any beneficial effect of treatment with this antiprogestin disappeared by the third treatment cycle (i.e. the 28 days following initiation of treatment on day 77 after insertion). Women taking antiprogestin reported, on average, bleeding and/or spotting on 38.2% ± 23.7 days during the 28 day period, whereas women in the placebo group recorded irregular bleeding on 28.7% ± 20.7 days during the third 28 day cycle. In fact, women in the placebo group reported a significantly lower percentage of days of bleeding and/or spotting during the third cycle.
Twenty-three percent (14/61) of women taking CDB-2914 reported a tendency to gain weight during the trial, compared with only 4% (2/25) of women in the control group. While this difference is statistically significant, according to patient characteristics collected at baseline, women who were randomized to the treatment group were more likely to have discontinued use of a previous contraceptive method due to weight gain.
There was no significant difference with regards to patient dissatisfaction with treatment, as implied by drug noncompliance. Further reports of blood loss improvement did not differ between the two groups. Similar numbers of women in each group requested removal of their LNG IUS during the trial.
26. Vitamin C supplementation versus placebo (prophylactic treatment for DMPA users; n= 1 study)
A single trial (Harel 2002) evaluated the effects of oral vitamin C supplementation on bleeding patterns among adolescents initiating DMPA use. Fifty-five adolescent girls (age 16 ± 1 years) were randomly assigned to one of four groups (three treatment groups and a placebo group); only one of the treatment groups was included as a possible prophylactic treatment for bleeding irregularities, the other two treatment groups were not included in the present analysis. The treatment group received 500 mg vitamin C plus placebo per day and the placebo group received 2 placebo tablets per day. Follow-up visits were scheduled at three and six months after the initial injection. There was no significant difference in the number of days of bleeding during the follow up period experienced by women in the treatment group, versus the placebo.
27. Antiprogestin and matrix metalloproteinase inhibitor versus placebo (therapeutic treatment for Implanon users; n= 1 study)
In a single trial (Weisberg 2009), Implanon users who experienced prolonged or frequent bleeding patterns were randomised to receive doxycycline 100 mg/twice daily for five days, with the addition of 25 mg mifepristone on the first day, or similar placebo. The trial implemented a 90-day treatment period, with a 90 day post-treatment follow-up period. Extracted data demonstrated a significant treatment benefit with respect to continued irregular bleeding during treatment; 1 of the 35 women randomized to receive the active treatment reported continued bleeding, compared with 11 of the 37 women who received placebo [RR 0.10; 95% CI 0.01, 0.71].
At 90 and 180 days following initiation of treatment, there were no differences in Implanon discontinuation rates between women receiving doxycycline and mifepristone and those receiving placebo, despite a tendency for improved continuation rates at 180 days in the treatment group [RR 0.49; 95% CI 0.09, 2.52] and [RR 0.33; 95% CI 0.09, 1.11], respectively.
The side effect of nausea/vomiting was reported slightly more frequently by women in the treatment group; however, this difference was not significant. Alternatively, fewer women in the treatment group reported headaches; again, this finding was not significant.
28. Estrogen and matrix metalloproteinase inhibitor versus placebo (therapeutic treatment for Implanon users; n= 1 study)
In a single trial (Weisberg 2009), Implanon users who experienced prolonged or frequent bleeding patterns were randomised to receive doxycycline 100 mg/twice daily combined with EE 20 μg/day for five days, or similar placebo. The trial implemented a 90-day treatment period, with a subsequent 90 day follow-up period. Extracted data demonstrated no treatment benefit with respect to the number of women reporting continued irregular bleeding during treatment; 14 of the 35 women randomized to receive the active treatment reported continued bleeding, compared with 11 of the 37 women who received placebo [RR 1.35; 95% CI 0.71, 2.55].
At 90 and 180 days following initiation of treatment, there were no differences in Implanon discontinuation rates between women receiving doxycycline and EE and those receiving placebo.
The number of women reporting the side effects of nausea/vomiting or headache was not different between treatment groups.
29. Estrogen versus placebo (prophylactic treatment for LNG IUS users; n= 1 study)
One recently published trial (Madden 2012) evaluated whether the application of a transdermal 0.1 mg estradiol patch decreased bleeding and spotting among new users of the LNG IUS. Overall, the trial enrolled 129 women initiating the use of the LNG IUS and randomly assigned them to three arms for twelve weeks of treatment (84 days). Forty-four women were assigned to the transdermal estradiol arm, 42 women received a 500 gm NSAID, and 43 women received a placebo identical to the NSAID. Comparisons between the NSAID and placebo arms are presented and analysed elsewhere in this review.
Women assigned to the transdermal estradiol group applied their patch the day following IUS insertion and used it continuously, changing the patch on a weekly basis, for the 12 week treatment period. Beginning the day after IUS insertion, the placebo group took their study medication twice daily for the first five days of each four week period during the 12 weeks of treatment. Trial participants were asked to complete study diaries to record the occurrence of bleeding and spotting as well as compliance with the study's protocol. Telephone follow-up was conducted at 4, 8 and 16 weeks, and an in-person follow-up visit was scheduled at 12 weeks.
Because the results were reported as medians , range and quartiles, current analysis could not be done , and the results presented as reported by the authors.During the entire treatment period of the trial, women using the estradiol patch reported a greater number bleeding/spotting days than the placebo group [median and range: 44 days (2-82 days) for estradiol patch arm versus 32 days (9-84 days) for placebo arm], however the difference was not statistically different (p-value = 0.15). The distribution of bleeding and spotting over the 12-week treatment period showed that women in the estradiol patch arm were significantly more likely to experience patterns of bleeding/spotting within the highest quartile (i.e., 54-84 days) compared with women who received placebo (40.9% versus 18.l %, p-value = 0.02). During the four week post-treatment period, there were no reported differences in bleeding/spotting between women in the estradiol patch or placebo groups.
Over the 12 treatment period, one woman in each group discontinued the use of the LNG-IUS due to dissatisfaction with the demands of the trial (patch arm) and IUS expulsion (placebo arm). One woman in the patch group discontinued her treatment due to headache complaints. A greater proportion of women in the estradiol patch arm reported dissatisfaction with their treatment compared with the placebo group both at 4 weeks (39.5% versus 11.6%, p-value=0.01) and 12 weeks follow-up (13.5% versus 0).
30. Non-steroidal anti-inflammatory drug versus placebo (prophylactic treatment for LNG IUS users; n= 1 study)
A recently published trial (Madden 2012) evaluated the prophylactic effect of naproxen in decreasing bleeding and spotting irregularities among new users of the LNG IUS. The trial enrolled 129 new users of the LNG IUS, and randomly assigned them to three arms for twelve weeks of treatment (84 days). Forty-two women were assigned to receive naproxen (500 gm), 43 women received a placebo identical to naproxen, and 44 women were assigned to a transdermal estradiol arm. Comparisons between the estradiol patch and the placebo arms are presented and analysed elsewhere in this review.
Beginning the day after IUS insertion, the naproxen and placebo group took their 500 gm study medication twice daily for the first five days of each four week period during the 12 weeks of treatment. Trial participants were asked to complete study diaries to record the occurrence of bleeding and spotting as well as compliance with the study's protocol. Telephone follow-up was conducted at 4, 8 and 16 weeks, and an in-person follow-up visit was scheduled at 12 weeks.
Because the results were presented as means, range and quartiles, current analysis could not be done per review methodology. The authors reported that over the entire treatment period, women who received naproxen reported fewer bleeding/spotting days than the placebo group [median and range: 27.5 days (5-83 days) naproxen arm versus 32 days (9-84 days) placebo arm], however the difference was not statistically different (p-value = 0.1). The distribution of bleeding and spotting over the 12-week treatment period showed that women taking naproxen were more likely to experience patterns of bleeding/spotting within the lowest quartile (i.e., 2-21 days) compared with women who received placebo (42.9% versus 16.3 %). During the four week post-treatment period, there were no reported differences in bleeding/spotting between women in either group.
Over the 12 week treatment period, two women who received naproxen discontinued use of the LNG IUS due to pregnancy and chest pain. A woman in the placebo group discontinued using her LNG-IUS due to IUS expulsion. Reports of dissatisfaction with treatment differed minimally between the naproxen or placebo groups at 4 weeks (9.5% versus 11.6%); however, more women taking naproxen were dissatisfied with the treatment at 12 weeks (11.4% versus 0).
In performing the original review it became clear that clinical trial authors reported efficacy outcomes in such divergent manners so as to make comparison of the outcomes across studies difficult or impossible; this remains the case at the time of this update. Due to the methodological differences among trials, very few could be combined in our analysis; therefore our findings primarily describe the results from analyses of individual studies. Data for some of the outcomes selected for the review were difficult to extract or interpret. In many studies discontinuation of the contraceptive method for bleeding reasons was not differentiated from discontinuation for other reasons. And, finally, the numbers of women in many of the trials were small, making the results difficult to interpret.
Several of the included studies were designed to evaluate the effects of estrogen administration on bleeding irregularities associated with Norplant or DMPA use. Estrogens may enhance those mechanisms that cause bleeding to cease, i.e. coagulation or tissue repair (Shaaban 1984 and Viegas 1988). Results were inconsistent, with ethinyl estradiol showing beneficial effects in stopping a current bleeding episode as reported in several of the studies, and significant improvements in a combined analysis of two trials among Norplant users (Alvarez-Sanchez 1996 and Boonkasemsanti 1996). According to Said (Said 1996), among DMPA users, intake of ethinyl estradiol stopped bleeding better than placebo during the treatment period; however, part of the data was reported as medians and therefore could not be incorporated into our analyses. The higher rates of study discontinuation related to side effects of estrogenic compounds (Diaz 1990, Alvarez-Sanchez 1996) should encourage providers to exercise caution in recommending these regimens to their patients with bleeding irregularities, particularly those with known sensitivity to estrogens.
It is difficult to draw any firm conclusions from the data related to the prophylactic use of estrogens to prevent bleeding irregularities in DMPA users. While the first of the three studies (El-Habashy 1970) demonstrated a reduction in unacceptable bleeding during treatment with diethylstilbestrol, the study included only small numbers of women and was found to be of only moderate quality, due to possible inadequacies in allocation concealment and outcome assessment binding. In fact, all of the trials in this category suffer from weaknesses in design or implementation, with high rates of discontinuations (23-38%) in two of the trials (Parker 1980 and Goldberg 2002, respectively). In two of the trials (El-Habashy 1970 and Parker 1980) therapies were tested that are no longer available for clinical use. The high rates of discontinuation and of non-compliance with the study protocol in the Goldberg study (Goldberg 2002) not only confuse the interpretation of the results so that they could not be incorporated into the present analysis, they also suggest that the tested therapy (transdermal estrogen delivered by means of a daily patch) would not be accepted by a large proportion of women.In the recent trial of Madden(Madden 2012)A greater proportion of women in the estradiol patch arm reported dissatisfaction with their treatment compared with the placebo group both at 4 weeks (39.5% versus 11.6%, p-value=0.01) and 12 weeks follow-up (13.5% versus 0).,
Combined oral contraceptives (ethinyl estradiol and levonorgestrel) were used to treat bleeding irregularities among Norplant users in two trials, with the rationale being that most family planning service delivery facilities would have such a therapy readily available (Alvarez-Sanchez 1996 and Witjaksono 1996). The two studies reported a beneficial effect of treatment in stopping bleeding, though the endpoints and data in the latter study were reported in such a way as to make incorporation in our analysis impossible. We might presume to conclude that the addition of a progestin to the treatment regimen offered no benefit over and above the effects of an estrogen alone, but that it did not compromise the safety or effectiveness of an estrogen-only therapy. One study evaluated the role of combined oral contraceptives in treating amenorrhea associated with the use of DMPA (Sadeghi-Bazargani 2006 ). These investigators reported that more women resumed menstruation with the use of this therapy, and fewer women discontinued the use of DMPA in comparison to placebo; these positive results were confirmed in the present analysis. However, it is difficult to draw any conclusion about this regimen as the type, dose and duration of use of the combined oral contraceptive was not reported; in addition, the sample size was small, with fewer than 25 women in each study group.
The use of an additional progestin to resolve bleeding irregularities in Norplant users met with limited success in a single study (Diaz 1990). While the study reported moderate improvements in bleeding in women using levonorgestrel compared with placebo, it suffered from high discontinuation rates, high rates of non-use of the treatment, even when required by the protocol, and other potential sources of bias. Because of the natural changes in bleeding patterns over the first year of Norplant use, the data describing the overall mean number of bleeding days in every treated bleeding interval (up to five in the year, but with a mean range of 2.2 to 3.1 treated cycles per woman per year) could not be included in our analyses. We could not compare these mean data with data on single intervals of treatment.
An anti-progestin (mifepristone) was used to treat bleeding among Norplant users in one trial (Cheng 2000). According to our analysis, users of mifepristone reported a significant decrease in bleeding during treatment at six months following initiation of treatment, but not before. This supports the authors' report that all women experienced a decrease in the frequency of bleeding over the course of the one-year study, but that the decrease was more gradual in the placebo group than for those women receiving mifepristone.
Anti-progestins have also been shown to be somewhat promising in the prevention of bleeding irregularities in DMPA (Jain 2003), minipill (Gemzell-Danielsson 2002 ), Norplant (Massai 2004) and LNG IUS users (Warner 2010). In the first two studies, the authors reported that women taking antiprogestins reported fewer cycles with extended periods (more than 14 days) of breakthrough bleeding or better cycle control, respectively, than did placebo users; however, these outcomes were not identified for the present review, and therefore the data could not be included in this analysis. Massai et al (Massai 2004) demonstrated acute, but not long-term, improvements in bleeding patterns in new Norplant users taking mifepristone.Warner 2010 reported similar results with the use of antiprogestin(CDB-2914) to reduce bleeding irregularities among new users of the LNG IUS. In contrast, mifepristone was not effective in stopping an episode of bleeding in women using Implanon (Weisberg 2006). In this trial, the addition of an estrogen to mifepristone was more effective than placebo in stopping an episode of bleeding. The data were presented in terms of 90-day reference periods, before and after the treatment; our analysis was not able to capture the data presented in this manner.
Glasier et al (Glasier 2002) and Jain et al (Jain 2003) have suggested that mifepristone may functionally inhibit progesterone, leading to up-regulation of endometrial estrogen receptors and a positive effect on bleeding patterns similar to exogenous estrogen treatment. In contrast, Grow and co-workers (Grow 1998) have demonstrated, primarily in non-human primates, that even though estrogen receptors are increased following mifepristone exposure, the receptors may not be transcriptionally active.
While anti-progestins have been shown in some trials to improve bleeding. The results of these studies need to be substantiated in larger, well-controlled trials; an effective dose and regimen need to be defined. In addition, the safety of such a regimen needs to be established, as the approach to antagonize the effect of the contraceptive progestin to achieve better bleeding patterns may potentially compromise the efficacy of the contraceptive method. In fact, one pregnancy was reported in the trial using the highest dose of mifepristone (Massai 2004).
The results of the single trial that was designed to evaluate the effects of a SERM (tamoxifen) on bleeding patterns in women using progestin-only contraceptive methods were quite promising in terms of effectiveness, safety, continuation of the contraceptive method and compliance with treatment (Abdel-Aleem 2005). This was the only regimen that demonstrated an effect that lasted longer than the period of treatment. Again, this result needs to be substantiated in larger trials, with longer periods of follow-up, before any clinical recommendation can be made. Grow et al hypothesized that SERMs may improve bleeding patterns disrupted by the use of progestin-only contraceptives by antagonizing the angiogenic effect of estrogen (Grow 1998).
Several other types of treatments have been shown to be somewhat effective in small trials, but the results have not been reproduced in larger studies, possibly demonstrating a overestimation of the beneficial effects of drugs in small studies. Vitamin E, for example, was effective in reducing the number of bleeding days during treatment in a pilot study conducted in Indonesia (Subakir 2000); these results were not replicated in a large multi-centre study of the same regimen, even in the same Indonesian centre (d'Arcangues 2004). The d'Arcangues et al study (d'Arcangues 2004) also failed to demonstrate the positive results of NSAIDs on bleeding patterns reported by Diaz et al (Diaz 1990), Kaewrudee et al (Kaewrudee 1999) , Nathirojanakun et al (Nathirojanakun 2006) and Madden (Madden 2012). These different results may be related to the use of different treatments - the studies that reported a positive effect of the treatment tested ibuprofen, as used by 21 women (Diaz 1990), mefenamic acid, in 34 women (Kaewrudee 1999) or the COX-2 inhibitor, valdecoxib, in 22 women (Nathirojanakun 2006); and naproxen in 42 new users of LNG IUS. In the larger trial, in which an NSAID was not effective, over 100 women who received aspirin were included in the analysis. On the other hand, the rationale for testing both Vitamin E and NSAIDs is scientifically compelling. As the angiogenic response in the endometrium of Norplant users has been found to be lower than in women with normal menstrual cycles (Subakir 2000), the disturbance in the angiogenic process, as well as an imbalance of pro- and antioxidant processes in the endometrium, may contribute to irregular bleeding in Norplant users. Supplementation with vitamin E may serve as an effective method of preventing membrane damage caused by oxygen radicals (Halliwell 1992) or of increasing endometrial angiogenic activity(Subakir 2000 ).
One small study have suggested that the antifibrinolytic compound, tranexamic acid, can have a short-term therapeutic effect on bleeding disturbances in Norplant users (Phupong 2006) .Tranexamic acid has been used around the world for over 20 years to treat heavy menstrual bleeding. Tranexamic acid, a synthetic lysine derivative, is an antifibrinolytic drug that prevents the breakdown of fibrin by competitively blocking binding sites of plasminogen.By slowing the process of dissolving the tiny clots that are formed as a result of bleeding, tranexamic acid can reduce the amount of bleeding (Lukes 2011). Small studies evaluated the effect of the matrix metalloproteinase inhibitor, doxycycline (DOX), in terminating an episode of prolonged bleeding in Implanon users. One pilot study showed a beneficial effect of DOX (Weisberg 2006). But these results were not replicated in a trial done in the same centre(Weisberg 2009) and in a more recent trial testing DOX to treat bleeding episodes among DMPA users (Abdel-Aleem 2012).The three trials used the same dose and regimen of DOX.
Implications for practice
Based on the results of this review, women may benefit to a degree from the interventions described, particularly with regard to cessation of an ongoing bleeding episode. Several regimens offer promise in regulating bleeding in the short term, but positive results need to be reproduced in larger scale trials. The results of the review do not support the routine clinical use of any of the treatment or preventive regimens to exert anything other than a short-term effect on the current bleeding episode; no medium- or long-term beneficial effects were described in any of the studies. The review was focused on pharmacologic interventions; however, it is acknowledged that proper counseling at the time of method initiation can help to prepare women for the bleeding irregularities that they may experience and improves method continuation rates.
Implications for research
Many women using progestin-only methods experience unacceptable bleeding disturbances, discontinue use, and are left without contraceptive protection or switch to a less effective method. It is essential that the family planning research community develop standardized methodologies for research and reporting in this field of study. If a common set of outcomes could be developed and widely utilized, studies could be more easily and effectively interpreted and compared, and the findings would more readily make their way into evidence-based practice, as appropriate. It is recommended that future studies attempt to collect data on blood loss using objective and validated measurement tools, such as the pictorial blood assessment scores.
Through the process of performing the review, it became clear to the authors that additional research directed towards the possible underlying mechanisms of bleeding among users of these products is required. Results from such studies would not only help to further identify potential therapeutic interventions, but would help to ensure that clinical studies and, eventually, treatments can be based on etiological findings.
The statistical advice and assistance of Barts J.A. Mertens, Department of Medical Statistics, Leiden University, the Netherlands and Dr Gilda Piaggio, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction are gratefully acknowledged, for their contributions to the original review.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Appendix A: Search strategy
(progestational hormones, synthetic or progesterone or contraceptives, oral, synthetic or contraceptives, oral , hormonal or progestational hormones or gestagen or progestogen only contracept* or progestin only contracept*) and (uterine, hemorrhage or amenorrhea or (vagina* near (bleed* or haemorrhag* or hemorrhag* or blood loss)) or ((uterus or uterine) near (bleed* or haemorrhag* or hemorrhag* or blood loss)) or spotting or ((irregular or prolonged or frequent or persistent or unpredictable or unscheduled or abnormal or breakthrough) near (bleed* or menstrual* or menses or blood loss or period or periods or haemorrhag* or hemorrhag*)) or menstrual disturbance* or menstrual disorder)
limited to Publication date From 2009/05/27 to 2012/05/24
(progestational hormones, synthetic or progesterone or progestin or contraceptives, oral, synthetic or contraceptives, oral , hormonal
or "progestational hormones" or gestagen or "progestogen only "contracept* or "progestin only" contracept* or progestogen*
or norgestrienone or norgestrel or ogyline or microlut or microval or mirena or norplant or levonova or microlutin or follistrel
or neogest or norgeston or postinor-2 or ovrette or velonorgestrel or norgestimate or "nomegestrol acetate" or "norethisterone acetate"
or "norethiserone enanthate" or "norethisterone enantate" or micronovum or primolut-nor or ocilan or micronor or noriday or norlutate
or milligynon or norfor or noristerat or norluten or gestakadin or sovel or conludag or nur-isterate or mini-pe or menzol or primolut-N
or sh420 or utovlan or aygestin or nor-qd or medroxyprogesterone acetate or depo-provera or depocon or farlutal or prodafem
or provera or depo-ralovera or ralovera or depo-prodasone or gestoral or prodasone or clinofem or clinovir or depo-clinovir or
g-farlutal or lutoral or perlutex or petogen or depo-progevera or progevera or cykrina or gestapuran or prodafem or amen or
curretab or cycrin or lynoestrenol or lynestrenol or orgametril or exluton or exlutona or exlutena or gestodene or etonogestrel or
implanon or ethynodiol diacetate or etynodiol or lutometrodiol or luteonorm or femulen or drospirenone or desogestrel or
dienogest or demegestone or lutionex or c"yproterone acetate" or andro-diane or androcur or cyprone or cyprostat or
chlormadinone or luteran or gestafortin or prostal or algestone or acetophenide or neolution depositum
or levonorgestrel OR Intrauterine devices, medicated OR levonorgestrel intrauterine device OR levonorgestrel intrauterine system OR levonorgestrel releasing intrauterine device OR levonorgestrel releasing intrauterine system) and (uterine, hemorrhage or amenorrhea or (vagina* near(bleed* or haemorrhag* or hemorrhag* or blood loss)) or ((uterus or uterine) near (bleed* or haemorrhag* or hemorrhag* or blood loss)) or spotting or ((irregular or prolonged or frequent or persistent or unpredictable or unscheduled or abnormal or breakthrough) near (bleed* or menstrual* or menses or blood loss or period or periods or haemorrhag* or hemorrhag*)) or menstrual disturbance* or menstrual disorder)
title/keyword- (progestin only contracept*/ progesterone only contracept*/oral contraceptives low dose/ progestins low dose/(contraceptive agents & (progestin*/progesterone*))/progestogne*/norgestrienone/norgestrel/ogyline/microlut/microval/mirena/norplant/levonova/microlutin/follistrel/neogest/norgeston/postinor-2/ovrette/velonorgestrel/norgestimate/nomegestrol acetate/norethisterone acetate/norethiserone enanthate/norethisterone enantate/micronovum/primolut-nor/ocilan/micronor/noriday/norlutate/milligynon/norfor/noristerat/norluten/gestakadin/sovel/conludag/nur-isterate/mini-pe/menzol/primolut-N/sh420/utovlan/aygestin/nor-qd/medroxyprogesterone acetate/depo-provera/depocon/farlutal/prodafem/provera/depo-ralovera/ralovera/depo-prodasone/gestoral/prodasone/clinofem/clinovir/depo-clinovir/g-farlutal/lutoral/perlutex/petogen/depo-progevera/progevera/cykrina/gestapuran/prodafem/amen/curretab/cycrin/lynoestrenol/lynestrenol/orgametril/exluton/exlutona/exlutona/exlutena/gestodene/etonogestrel/implanon/ethynodiol diacetate/etynodiol/lutometrodiol/luteonorm/femulen/drospirenone/desogestrel/dienogest/demegestone/lutionex/cyproterone acetate/andro-diane/androcur/cyprone/cyprostat/chlormadinone/luteran/gestafortin/gestafortin/prostal/algestone/acetophenide/neolution depositum) & (bleed*/ menstruation disorders/haemorrhage/hemorrhage/spotting) & treat*
abstract - (progestin only contracept*/ progesterone only contracept*/oral contraceptives low dose/ progestins low dose/(contraceptive agents & (progestin*/progesterone*))/progestogne*/norgestrienone/norgestrel/ogyline/microlut/microval/mirena/norplant/levonova/microlutin/follistrel/neogest/norgeston/postinor-2/ovrette/velonorgestrel/norgestimate/nomegestrol acetate/norethisterone acetate/norethiserone enanthate/norethisterone enantate/micronovum/primolut-nor/ocilan/micronor/noriday/norlutate/milligynon/norfor/noristerat/norluten/gestakadin/sovel/conludag/nur-isterate/mini-pe/menzol/primolut-N/sh420/utovlan/aygestin/nor-qd/medroxyprogesterone acetate/depo-provera/depocon/farlutal/prodafem/provera/depo-ralovera/ralovera/depo-prodasone/gestoral/prodasone/clinofem/clinovir/depo-clinovir/g-farlutal/lutoral/perlutex/petogen/depo-progevera/progevera/cykrina/gestapuran/prodafem/amen/curretab/cycrin/lynoestrenol/lynestrenol/orgametril/exluton/exlutona/exlutona/exlutena/gestodene/etonogestrel/implanon/ethynodiol diacetate/etynodiol/lutometrodiol/luteonorm/femulen/drospirenone/desogestrel/dienogest/demegestone/lutionex/cyproterone acetate/andro-diane/androcur/cyprone/cyprostat/chlormadinone/luteran/gestafortin/gestafortin/prostal/algestone/acetophenide/neolution depositum) & (bleed*/ menstruation disorders/haemorrhage/hemorrhage/spotting) & treat*
disorders/haemorrhage/hemorrhage/spotting) & treat*
s progestational hormones, synthetic
s low dose oral contraceptive
s progestin(n)only or progesterone(n)only or progestogen(n)only and contracep?
s progestin(n)only or progesterone(n)only or progestogen(n)only) and oral contraceptive agent
s (progestin(n)only or progesterone(n)only or progestogen(n)only) and oral contraceptive agent
s s1 or s2 or s3 or s4 or s6
s uterus bleeding
s (uterus or uterine)(n)(bleed? or haemorrhag? or hemorrhag? or "blood loss)
s (uterus or uterine)(n)(bleed? or haemorrhag? or hemorrhag? or "blood loss")
s (irregular or prolonged or frequent or persistent or unpredictable or unscheduled or abnormal or breakthrough)(n)(bleed? or menstrual? or menses or "blood loss" or period or periods or haemorrhag? or hemorrhag?)
s menstrual disorder
s menstruation disorder
s menstrual irregularity
s s8 or s9 or s11 or s12 or s13 or s14 or s15 or s16
s lng ius
s s7 or s18 or s19
s s17 and s20
e clinical trial
s r1, r3:r10
s random? or allocat?
s s22 or s23
s s21 and s24
s s25 and pd=20090706:20120613
(progest* only contracept* or oral contraceptives low dose or progestins low dose or levonorgestrel or "LNG IUS" or levonorgestrel IUS or levonorgestrel NEAR/1 releasing or levonorgestrel IUD) AND (bleed* or menstruation disorders or haemorrhage or hemorrhage or spotting) AND treat*
progest* or progestinas or progestogens or progesterona or gestagen or levonorgestrel or levanogestrel [Words] and bleeding or sangria or sangramento or haemorrhage or hemorrhage or hemorragia or hemorragia uterina or menstrual or amenorrhea or amenorrea or amenorreia [Words]
Last assessed as up-to-date: 15 May 2012.
Protocol first published: Issue 1, 2002
Review first published: Issue 2, 2007
Contributions of authors
HAA, CDA, AMG had the idea. HAA prepared the protocol with comments from CDA, KV and AMG. KV. In this updated review,KV, MG and HAA extracted the data. HAA, MG and KV prepared and updated the review. CDA reviewed the updated review.
Declarations of interest
CDA and HAA have conducted research in this area and have authored papers included in the review.
Sources of support
- Department of Obstetrics and Gynecology, Assiut University Hospital, Assiut, Egypt.
- HRP-UNDP/UNFPA/WHO/World Bank Special Programme in Human Reproduction, Geneva, Switzerland.
- No sources of support supplied
Medical Subject Headings (MeSH)
Contraceptive Agents, Female [adverse effects; *therapeutic use]; Contraceptives, Oral, Synthetic [therapeutic use]; Delayed-Action Preparations [therapeutic use]; Drug Combinations; Levonorgestrel [adverse effects]; Medroxyprogesterone Acetate [therapeutic use]; Menstruation Disturbances [chemically induced; *drug therapy]; Progestins [*adverse effects]; Randomized Controlled Trials as Topic
MeSH check words
* Indicates the major publication for the study