Treatment of Vaginal Bleeding Irregluarities Induced by Progestin Only Contraceptives

Treatment of vaginal bleeding irregularities induced by
progestin only contraceptives (Review)
Abdel-Aleem H, d’Arcangues C, Vogelsong KM, Gaffield ML, Gülmezoglu AM
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 7
http://www.thecochranelibrary.com
Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) i

[Intervention Review]
Treatment of vaginal bleeding irregularities induced by

progestin only contraceptives
Hany Abdel-Aleem1 , Catherine d’Arcangues2 , Kirsten M Vogelsong3 , Mary Lyn Gaffield4 , A Metin Gülmezoglu5
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt. 2 Own Consultancy,
Prevessin-Moens, France. 3 Bill and Melinda Gates Foundation, Seattle, Washington, USA. 4 Department of Reproductive Health and
Research, World Health Organization, Geneva 27, Switzerland. 5 UNDP/UNFPA/WHO/World Bank Special Programme of Research,
Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health
Organization, Geneva, Switzerland
Contact address: Hany Abdel-Aleem, Department of Obstetrics and Gynecology, Faculty of Medicine, Assiut University Hospital,
Assiut, Assiut, 71511, Egypt. hany.abdelaleem@yahoo.com. haleem@aun.edu.eg.
Editorial group: Cochrane Fertility Regulation Group.

Publication status and date: Edited (no change to conclusions), published in Issue 7, 2013.
Review content assessed as up-to-date: 15 May 2012.
Citation: Abdel-Aleem H, d’Arcangues C, Vogelsong KM, Gaffield ML, Gülmezoglu AM. Treatment of vaginal bleeding irregular-
ities induced by progestin only contraceptives. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD003449. DOI:
10.1002/14651858.CD003449.pub4.
ABSTRACT
Background
Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience
irregular vaginal bleeding when using them. Current treatments to control these bleeding problems are not sufficiently effective.
Objectives
We evaluated preventive and therapeutic approaches to normalise bleeding irregularities associated with the use of progestin-only
contraceptives.
Search methods
Literature was identified through database searches, reference lists, organisations and individuals, covering the period until May-June
2012.
Selection criteria
Trials with random or systematic allocation, testing interventions for the prevention or treatment of bleeding irregularities associated
with the use of progestin-only contraceptives were eligible.
Data collection and analysis
Results are expressed as relative risks (RR) with 95% confidence interval (CI) for categorical data and as weighted mean difference
(WMD) with 95% CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects
model (quantitative) or did not produce a summary estimate (qualitative).
Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 1
Main results
Thirty-three randomised controlled trials enrolling 3677 participants were included. Two thirds of the trials were determined to reflect
low to moderate risk of bias.
Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA and Norplant users. However, treatment
frequently led to more discontinuation due to gastrointestinal upset.
Combinations of oral ethinyl estradiol and levonorgestrel improved bleeding patterns in Norplant users, but method discontinuation
rates were unchanged. One trial reported successful use of combined oral contraceptives in treating amenorrhea among DMPA users.
Norplant users, but not Implanon users, administered the anti-progestin mifepristone reported fewer days of bleeding during treatment
than those given placebo. Mifepristone used monthly by new Norplant acceptors reduced bleeding, when compared to placebo.
A variety of NSAIDS have been evaluated for their ability to treat abnormal bleeding, with mixed results.
Norplant users receiving SERM (tamoxifen) had less unacceptable bleeding after treatment and were more likely to continue using
Norplant than those receiving placebo.
Tranexamic acid, mifepristone combined with an estrogen and doxycycline were more effective than placebo in terminating an episode
of bleeding in women using progestin-only contraceptives, according to three small studies.
Authors’ conclusions
Some women may benefit from the interventions described, particularly with cessation of current bleeding. Several regimens offer
promise in regulating bleeding, but findings need to be reproduced in larger trials. The results of this review do not support routine
clinical use of any of the regimens included in the trials, particularly for long-term effect.
PLAIN LANGUAGE SUMMARY
Evaluation of treatments for vaginal bleeding induced by progestin-only contraceptives
As the use of progestin-only methods of contraception continues to increase worldwide, the problem of vaginal bleeding disturbances
these methods induce is becoming of increasing public health relevance.Since this adverse effect limits method’s acceptability, and leads
to loss of compliance. Some women may benefit to some degree from some interventions tested. However the evidence reviewed is
not strong enough to recommend routine use of any of the regimens included in the trials, particularly for long-term effects. Positive
results need to be reproduced in larger scale trials.
BACKGROUND injectable contraceptive currently available, norethisterone enan-

Description of the condition thate, is estimated to be used by fewer than one million women.
Over the past 30 years, the number of users of progestin-only Additional progestin-only contraceptive methods are based on sev-
methods of contraception has been increasing steadily world- eral delivery systems: subcutaneous implants, intra-uterine sys-
wide and is estimated to be over 20 million. The method most tems, vaginal rings and oral preparations. Five implant systems are
widely used is the injectable depot medroxy-progesterone acetate available to family planning programmes; the most widely-used of
(DMPA), first registered in the late 1960s in some countries. Its these was the six capsule levonorgestrel-releasing implantable sys-
approval for contraceptive use by the United States Food and Drug tem, Norplant. This method was introduced in 1983, and has been
Administration in 1992 increased access to the method world- used by approximately six million women; post-registration stud-
wide, through new registrations; approximately 13 million women ies have demonstrated that the method is highly effective over a pe-
worldwide use DMPA for contraception. The other progestin-only riod of seven years. Its manufacture was discontinued in 2002.The
two-rod levonorgestrel-releasing implantable system, Jadelle, is ef- In the absence of complete understanding of the underlying mech-
fective for five years and was first registered for this length of use in anisms leading to vaginal bleeding irregularities, there are varia-
the year 2000. Two generic products, designed to imitate the per- tions in clinical practice. In the early 1980s, a survey was con-
formance of these two implants, are made in China and are known ducted on the management of progestin-associated menstrual
as Sino-implant (I) and (II), respectively. A single-implant system disturbances among physicians and organizations (Fraser 1983).
that has been available since 1997, Implanon releases etonogestrel There were 35 responses from 20 countries, most reporting ex-
and is effective for a period of 3 years and is used by approximately perience with DMPA, and three with additional experience with
six million women worldwide. The levonorgestrel-releasing intra- NET-EN. Fourteen years later, another survey (Nutley 1997) was
uterine system, Mirena, has been available since 1990 and is cur- conducted among family planning providers and researchers on
rently used by around ten million women worldwide. The pro- the treatment regimens they used for progestin-associated bleeding
gesterone-releasing vaginal ring, Progering, designed for use by disturbances. Sixty four responses from 32 countries were received.
breast feeding women, has been available in limited markets since The second survey collected information based on experience with
the late 1990s. Use of progestin-only oral preparations remains injectable, implantable and oral progestin-only methods. Both sur-
limited, despite being appropriate for lactating women and others veys documented a wide variability of treatment regimens offered
who do not tolerate estrogens. Other progestin-only methods are to women, ranging from estrogens, combined oral contraceptives,
being developed, such as transdermal patches and new injectable, progestins, non-steroidal anti-inflammatory agents, to vitamins,
implantable and intra-uterine systems. iron and anxiolytic agents.
Progestin-only contraceptive methods are highly effective ,safe and How the intervention might work
the long-acting properties of several delivery systems facilitate their
use. However, despite differences in their primary mechanisms of Because the exact etiology of vaginal bleeding irregularities associ-
action, all induce major uterine bleeding disturbances in a signifi- ated/induced by progestin-only contraceptives is not completely
cant number of users. Data from clinical trials demonstrate that, at elucidated, different interventions are targeting different possible
one year of use, fewer than 10% of DMPA and Mirena users and mechanisms.For instance; estrogens may enhance those mecha-
only 25% of Norplant users experience regular monthly bleeding, nisms that cause bleeding to cease, i.e. coagulation or tissue repair
while others experience a variety of patterns ranging from infre- (Shaaban 1984 and Viegas 1988),the anti-progestin (mifepristone)
quent bleeding and amenorrhea to irregular, frequent or prolonged may functionally inhibit progesterone, leading to up-regulation
bleeding. These patterns are all classified as breakthrough bleeding of endometrial estrogen receptors and a positive effect on bleed-
and have been discussed in several publications (Newton 1994, ing patterns similar to exogenous estrogen treatment(Jain 2003),
Fan 1996, Suvisaari 1996, Affandi 1998, Fraser 1998,). This side SERMs(tamoxifen) may improve bleeding patterns disrupted by
effect is the primary reason that women give for discontinuing use the use of progestin-only contraceptives by antagonizing the an-
of these methods and accounts for 40-70% of termination from giogenic effect of estrogen (Grow 1998) and the antifibrinolytic
clinical trials (d’Arcangues 1992, Datey 1995,; Adeyemi 2012). agent(tranexamic acid) can reduce the amount of bleeding through
There seem to be great variations in the tolerance that women have slowing the process of dissolving the tiny clots that are formed as
for these disturbances. In a multicenter clinical trial of DMPA, a result of bleeding (Lukes 2011).
for example, users in Egypt, Jamaica and Thailand reported sim-
Why it is important to do this review
ilar rates of amenorrhea. In Egypt, 27% of women discontinued
DMPA use for this reason, while none did so in Thailand or Ja- This wide variation in treatments given to women, and the uncer-
maica (Said 1987). tainty about the potential benefits or risks of individual treatments,
highlight the importance of conducting a rigorous and compre-
Individual women respond differently to the use of progestin-
hensive review of the different treatments for vaginal bleeding ir-
only methods. Bleeding effects may also vary according to the
regularities associated with progestin-only contraceptives.
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 OBJECTIVES
bleeding, but later on this pattern is replaced by increasing periods
of amenorrhea. A reasonable clinical goal would be to provide The purpose of this review is to evaluate prophylaxis and treatment
an intervention to assist women in managing any irregularities in of bleeding irregularities associated with the use of progestin-only
bleeding - thus continuing the use of their chosen contraceptive contraceptives.
method - until the time when their bleeding becomes more regular
or until they experience amenorrhea.
Description of the intervention METHODS

Criteria for considering studies for this review 1. Discontinuation of the contraceptive method
2. Discontinuation of the treatment
a. Discontinuation due to side-effects
Types of studies b. Discontinuation due to lack of improvement
3. Any side-effect of treatment
Trials designed to test regimens to treat or prevent bleeding irreg-
4. Patient dissatisfaction with treatment
ularities associated with the use of progestin-only contraceptive
5. Blood loss during treatment
methods were considered for inclusion. Studies were required to
Outcome measures were assessed during treatment and/or at the
use random or systematic (i.e. alternation) methods of allocation.
end of treatment, to evaluate short-term effects, and at varying
Studies employing a cross-over design were not eligible for inclu-
intervals following discontinuation of treatment, to evaluate long-
sion.
term effectiveness, according to the study design.
Types of participants
Women using progestin-only contraceptives were the participants Search methods for identification of studies
of the studies included in this review. These comprise: The search included:
1. Women experiencing vaginal bleeding irregularities i.e. bleed- 1. ELECTRONIC DATABASES
ing/spotting, irregular bleeding, prolonged bleeding, frequent a. MEDLINE using OVID or SilverPlatter for the years 1966-
bleeding or amenorrhoea. The trialists’ definitions of these condi- 2006; searches were updated using Pubmed through May 2012.
tions were accepted. b. EMBASE using OVID for the years 1980-2006; EMBASE
2. Women not experiencing vaginal bleeding irregularities but ac- through Elsevier for years 2006 - 2012.
cepting prophylactic treatment. These women would be likely to The methodological search filter for high sensitivity in identify-
be enrolled as they start using the progestin-only contraceptive ing randomised controlled trials in MEDLINE, parts I and II
method. (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
Types of interventions search filter was adapted for use in searching EMBASE.
Drugs used to prevent or treat bleeding irregularities in women c. Popline was searched throughJune 7, 2012
using progestin-only contraceptives. These are likely to include: d. The Cochrane Central Register of Controlled Trials (CEN-
1. Estrogens TRAL), which includes controlled trials identified from electronic
2. Progestins databases as well as hand searching of relevant journals.
3. Combined oral contraceptives e. LILACS ( Literatura Latino Americana e do Caribe em Ciências
4. Nonsteroidal anti-inflammatory drugs da Saúde) which covers Latin American and Caribbean literature
5. Antioxidants in Spanish, Portugese and English was searched with the same
6. Antifibrinolytic agents search terms.
7. Antiprogestins/progesterone receptor modulators The drug classes and individual names for progestin-only contra-
8. Selective estrogen receptor modulators ceptives, including their proprietary names used in different coun-
9. Antiangiogenesis agents tries where known, were combined with terms describing vaginal
10 Matrix metalloproteinase inhibitors bleeding irregularities in order to identify treatment interventions.
11. Others
12. Combinations of the above The following subject search terms were combined:
#1 explode PROGESTATIONAL-HORMONES-SYNTHETIC
The dose, duration and frequency of treatment and length of fol- #2 explode PROGESTERONE
low-up should be specified. #3 explode CONTRACEPTIVES-ORAL-SYNTHETIC
#4 CONTRACEPTIVES-ORAL-HORMONAL
#5 PROGESTATIONAL-HORMONES
Types of outcome measures #6 gestagen
The primary outcome of this review is the effectiveness of pro- #7 progestogen only contracep* OR progestin only contracep*
phylactic or therapeutic interventions to prevent or treat bleeding #8 progesterone OR progestogen* OR norgestrienone OR
irregularities, as defined by an improvement in irregular bleeding. norgestrel OR ogyline OR microlut OR microval OR mirena OR
Trials using objective or subjective methods for assessing bleeding norplant OR levonova OR microluton OR follistrel OR neogest
were eligible. OR norgeston OR postinor-2 OR ovrette OR levonorgestrel OR
Additional outcomes included: norgestimate OR nomegestrol acetate OR norethisterone acetate

OR norethisterone enanthate OR norethisterone enantate OR mi- Two reviewers (HAA and KV) initially assessed the results of the
cronovum OR primolut-nor OR locilan OR micronor OR nori- search by checking the titles and the abstracts where available.
day OR norlutate OR milligynon OR norfor OR noristerat OR When unsure about the relevance or the methodology, they re-
norluten OR gestakadin OR sovel OR conludag OR nur-isterate quested and reviewed full reports. Reports of studies using a ran-
OR mini-pe OR menzol OR primolut-N OR sh420 OR utovlan dom or quasi-random allocation and evaluating the interventions
OR aygestin OR nor-qd OR medroxyprogesterone acetate OR described here were critically appraised for inclusion.
depo-provera OR depocon OR farlutal OR prodafem OR provera A data extraction form was developed, as described in the Cochrane
OR depo-ralovera OR ralovera OR depo-prodasone OR gestoral Handbook, for standardisation of the data extraction. Trials were
OR prodasone OR clinofem OR clinovir OR depo-clinovir OR reviewed for methodological quality based on concealment of al-
g-farlutal OR lutoral OR perlutex OR petogen OR depo-progev- location, outcome assessment blinding and drop out rates. If all
era OR progevera OR cykrina OR gestapuran OR prodafem OR of the criteria were met, there was considered to be a low risk of
amen OR curretab OR cycrin OR lynoestrenol OR lynestrenol bias (validity criteria score A). In cases where one or more criteria
OR orgametril OR exluton OR exlutona OR exlutena OR gesto- were partly met, for example if the trialists reported that the study
dene OR etonogestrel OR implanon OR ethynodiol diacetate OR was double blind, but didn’t report any concealment approach,
etynodiol diacetate OR lutometrodiol OR luteonorm OR femulen there was considered to be a moderate risk of bias (validity criteria
OR drospirenone OR desogestrel OR dienogest OR demegestone score B). If one or more of the criteria was not met, if allocation
OR lutionex OR cyproterone acetate OR andro-diane OR an- concealment or outcome assessment were not blinded, or if the
drocur OR cyprone OR cyprostat OR chlormadinone acetate OR study participant drop-out rate was more than 10%, studies were
luteran OR gestafortin OR prostal OR algestone acetophenide given a validity criteria score of C.
OR neolution depositum OR levonorgestrel OR lng ius There were no language restrictions for inclusion of trials. Ab-
#9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 stracted data were entered into Review Manager software and
#10 explode UTERINE-HEMORRHAGE analysed. Studies that enrolled women who were using any
#11 AMENORRHEA levonorgestrel-releasing subcutaneous implant (either the 2-rod
#12 vagina* NEAR (bleed* OR haemorrhag* OR hemorrhag* OR Jadelle system or the 6-rod Norplant system) were combined, since
blood loss) these methods release the same hormone at the same daily rate.
#13 uter* NEAR (bleed* OR haemorrhag* OR hemorrhag* OR Otherwise, studies that enrolled women who were using different
blood loss) contraceptive methods were not combined, due to the different
#14 spotting primary mechanisms of contraceptive action of the various meth-
#15 (irregular OR prolonged OR frequent OR persistent OR un- ods, and their differing effects on bleeding patterns. Since the types
predictable OR unscheduled OR abnormal OR breakthrough) and mechanisms of pharmaceutical agents used were different and
NEAR (bleed* OR menstrual* OR menses OR blood loss OR the desired outcomes of treatment differed between trials (for ex-
period OR periods OR haemorrhag* OR hemorrhag*) ample induction of regular menses or of amenorrhoea), different
#16 menstrual disturbance* groups of agents were not combined in a single analysis. Therefore,
#17 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 three main variables were identified in the comparison plan: the
#18 #9 AND #17 contraceptive method, the intervention, and the prophylactic or
therapeutic nature of the intervention. Few trials could be com-
(N.B. Upper case denotes controlled vocabulary, which comprise bined and we conducted the analyses with this consideration in
Thesaurus terms applied by the database indexers, and lower case mind.
denotes free-text terms, which are used by the authors of the stud- Data regarding participant drop out rates, loss to follow up and
ies). reasons for early discontinuations were recorded and presented
The search strategies of the different data bases are shown in Ap- in the table of included studies. Study participant characteristics,
pendix A. treatment interventions, length of follow-up and outcome mea-
2. Reference lists of trials identified and relevant review articles sures were recorded. Trial characteristics such as type of trial, study
were scrutinized for any additional trials not retrieved with the duration and setting where the trials were conducted were also
database searches listed above. recorded.
3. Researchers active in the field were contacted for possible un- The data were extracted separately by two reviewers (HAA and KV)
published studies or data. and discrepancies or disagreements were resolved by discussion and
The searches included all languages. 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
Data collection and analysis interval (CI) for continuous data, using a fixed-effect approach

where possible. When we encountered heterogeneity (visual or These included estrogens alone in various formulations (ethinyl
statistical) we used the random-effects model (quantitative) or did estradiol,17-beta estradiol, diethylstilbestrol, oestrone sulphate,
not produce a summary estimate (qualitative). 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,
RESULTS 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
Description of studies 2006). An antiprogestin was combined with an estrogen as a
method to treat irregular bleeding in two trials (Weisberg 2006,
This review included 33 randomised (n=32) or systematically al-
Weisberg 2009). A capillary protecting venotonic drug (regis-
located (n=1) controlled trials (RCTs), conducted in 17 countries
tered in France as Cyclo 3, containing extract of Ruscus aculeatus
(China, Indonesia, Iran, Pakistan, the Philippines and Thailand in
with ascorbic acid and hesperidin methyl chalcone) was used thera-
Asia; Tunisia and Egypt in Africa; France, the Netherlands, Swe-
peutically in one trial (Monteil-Seurin 1985). In two trials (Subakir
den, Switzerland and the United Kingdom in Europe; the United
2000 and d’Arcangues 2004), vitamin E was used therapeuti-
States of America in North America; Chile and the Dominican Re-
cally. Non-steroidal anti-inflammatory drugs (NSAIDs) were
public in Latin America; and Australia). Studies were conducted at
used therapeutically in eight trials (Archer 2008, Buasang 2009,
family planning clinics, hospitals and university research centres.
Diaz 1990, Kaewrudee 1999, d’Arcangues 2004, Nathirojanakun
2006, Phaliwong 2004 and Tantiwattanakul 2004). The thera-
Contraceptives used:
peutic effects of combined Vitamin E and NSAIDs were eval-
Twelve of the included studies enrolled women using Norplant as
uated in a single trial (d’Arcangues 2004). A selective estrogen
their contraceptive method. New Norplant users, as well as women
receptor modulator (SERM) was used therapeutically in one
using the method for one to 43 months were enrolled; most of the
trial (Abdel-Aleem 2005). An antifibrinolytic agent was used
studies limited enrolment to women using the method for less than
in two trials (Phupong 2006, Senthong 2009). A matrix met-
one year. Twelve studies were conducted to evaluate interventions
alloproteinase inhibitor (MMPI) alone was used in three trials
in women using the injectable DMPA. Two of these enrolled new
(Abdel-Aleem 2012, Weisberg 2006, Weisberg 2009). One trial
users, with the aim of evaluating interventions to prevent bleeding
evaluated the effects of combined MMPI and estrogen treatment
irregularities; the remaining studies enrolled women who had been
( Weisberg 2009); this same study also evaluated MMPI com-
using the method for one to 18 months. In three trials, women
bined with an antiprogestin.
used progestin-only pills; the duration of use was at least one
Four types of interventions were tested for their effects to pre-
month in one study and was not defined in the other two studies.
vent bleeding irregularities in users of progestin-only contracep-
Three trials recruited women who had been using Implanon for a
tives. These included estrogens alone (estradiol acetate, diethyl-
period of more than two months. Two studies enrolled new users
stilbestrol, 17-beta estradiol, quinesterol) as used prophylactically
of the Mirena LNG-IUS. One study was conducted to evaluate
in five trials (Dempsey 2010, El-Habashy 1970, Goldberg 2002;
treatment of irregular bleeding in Jadelle users.
Madden 2012 and Parker 1980). Anti-progestins were used pro-
Characteristics of participants:
phylactically in four trials (Gemzell-Danielsson 2002 , Jain 2003,
The age of women included in these trials generally was in the range
and Massai 2004 and Warner 2010). The effects of vitamin C
of 20 to 30 years; however, many of the studies’ inclusion criteria
in preventing bleeding irregularities in new DMPA users were
allowed for the enrolment of women up to age 45.. Two studies
evaluated in a single four-arm trial (Harel 2002). In addition, a
(Subakir 2000, and Weisberg 2006) included women 18 to 40
trial of new LNG-IUS users provided an NSAID for prophylaxis
years old. One study (Harel 2002) specifically enrolled adolescent
(Madden 2012).
girls; the mean age of participants in this trial was 16 ± 1 years.
All trials except (Dempsey 2010) were placebo-controlled. Twenty
The parity of women recruited in the trials was reported in only
four trials included a single intervention arm, while nine trials were
13 trials and ranged between zero and five. The body weight of
designed to test the effects of more than one intervention, singly
study participants was reported in 11 trials and mean body weights
or in combination. In two trials (El-Habashy 1970 and Parker
were reported in the range between 44 and 73 kg. Height was not
1980) the interventions tested, diethylstilbestrol and quinesterol,
mentioned in the majority of the trials, but nine studies reported
respectively, are no longer used in clinical practice, for any in-
the body mass index; in these trials BMI ranged from 21 to > 30
dication. In addition to the range of types of interventions, the
kg/m2.
treatments were used in different doses and according to different
Interventions:
dosing schedules, and study participants were followed according
There were 18 types of interventions tested in the trials.
to diverse schedules, for varying lengths of time.
Fourteen interventions were tested as therapeutic treatments.

Duration of Follow-Up: assessed as mentioned above, in the methods section, with va-
The duration of follow-up varied among the trials, from less than lidity criteria scores based on allocation concealment, outcome
three months to eighteen months. Most trials were designed to assessment blinding and number/percent of study discontinua-
test the short-term effects of the interventions, with only eight tions. The overall assessment of risk of bias is shown in (Figure
trials treating or following participants for longer than six months 1). According to these criteria, 10 of the trials were assigned
(Archer 2008, Parker 1980, Diaz 1990, Said 1996, Cheng 2000, “A” validity criteria scores with low risk of bias ( Abdel-Aleem
Goldberg 2002, Massai 2004 and d’Arcangues 2004). The longest 2005,Archer 2008, Buasang 2009, Cheng 2000, Kaewrudee
duration of follow-up, as reported in two studies (Archer 2008, 1999, Nathirojanakun 2006, Phaliwong 2004, Phupong 2006,
Said 1996) was one year and up to 18 months, respectively ; how- Senthong 2009 and Weisberg 2006). In these trials, allocation
ever, the long-term results were not reported. concealment was considered to be adequate, outcome assessment
Outcome measures: blinding was achieved and fewer than 10% of the enrolled women
Although nearly all trials were designed to evaluate the effects of discontinued prior to the end of the study(Figure 2). There
treatment on bleeding episodes as a primary outcome, the au- were 12 trials that were considered to be at moderate risk of
thors reported the outcome in different ways, including cessation bias and were therefore given validity criteria scores of “B”. In
of bleeding, number of bleeding days during treatment, number many of these studies, the allocation concealment was unclear
of bleeding days after treatment, number of days of treatment re- ( Boonkasemsanti 1996, Jain 2003, Johannisson 1982, Massai
quired before bleeding stopped, percent of women with bleeding 2004, Subakir 2000). The outcome assessment blinding was un-
free intervals of more than a given number of days, percent of clear or inadequate in three of these trials ( El-Habashy 1970, Jain
women with acceptable bleeding, and others. Moreover, the data 2003, Johannisson 1982 ).In two trials the drop out rate was >10%
were presented in different ways including means, medians, and but less than 15%(Abdel-Aleem 2012,Weisberg 2009). Eleven tri-
percentages. Other types of outcome measures included discon- als were given a validity criteria score of “C”, meaning that the
tinuation of the treatment, discontinuation of the contraceptive study may be subject to a high risk of bias (Alvarez-Sanchez 1996,
method, side effects due to treatment, dissatisfaction with treat- d’Arcangues 2004, Dempsey 2010,Gemzell-Danielsson 2002,
ment and, in a few studies, blood loss during treatment. Diaz 1990, Goldberg 2002,Madden 2012, Monteil-Seurin 1985,
Due to the lack of consistency in study design, outcome measures, Parker 1980, Said 1996 and Witjaksono 1996).In all these trials
and statistical reporting, very few studies could be combined in at least two of the criteria were unmet or not clear or the drop
the analyses. 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
Risk of bias in included studies be of good quality recruited 855 (23%) of 3,677 women enrolled
in all included trials.
This review included 33 trials. The methodological quality was
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 or spotting days within the 20 days following a 10-day EE treat-
1. Estrogen versus placebo (therapeutic treatment for LNG ment period were reported by Archer et al (Archer 2008).
subcutaneous implant users; n=5 studies) Based on our analysis of data reported by Alvarez-Sanchez 1996,
In five of the included studies, women reporting bleeding irregu- women receiving estrogen treatment appeared to be less likely to
larities while using Norplant were administered an estrogen formu- discontinue the use of Norplant for bleeding irregularities than
lation and followed for resolution of symptoms (Alvarez-Sanchez were those receiving placebo, though the overall effect was not
1996, Archer 2008, Boonkasemsanti 1996, Diaz 1990, and significant, as only one woman discontinued for this reason. Diaz
Witjaksono 1996). Together, these studies recruited 166 women 1990 did not report any method discontinuations for bleeding ir-
in the respective estrogen treatment arms and 185 women in regularities. Nausea or gastrointestinal discomfort was commonly
placebo groups; of these, data from 147 estrogen-treated women reported in the former study: only two of 46 participants receiving
and 173 placebo-treated women were included in the analyses. placebo reported such side effects, whereas 17 of 43 receiving estro-
Treatments included ethinyl estradiol (EE) tablets in four studies gen complained of gastric upset [RR 9.09, 95% CI 2.23, 37.06].
(Alvarez-Sanchez 1996, Archer 2008, Diaz 1990 and Witjaksono In the Diaz 1990 study, 5 of 13 study discontinuations in the es-
1996) and an estradiol patch in the fifth (Boonkasemsanti 1996). trogen group were associated with gastric intolerance, while none
The efficacy of the various treatments was reported in different of the women in the placebo group discontinued from the study
manners in these studies. In Alvarez-Sanchez 1996, the primary for this reason. Alvarez-Sanchez 1996 reported discontinuation of
outcomes included whether or not bleeding stopped within three treatment due to gastralgia or nausea in 2 of 50 women receiving
days of the initiation of treatment and the number of bleeding days treatment and none of the women in the placebo group. When
during the 20-day treatment interval. Archer et al (Archer 2008) the data for these studies were combined, it was clear that women
reported the main study outcomes as being the mean duration receiving estrogen tended to be more likely to discontinue their
(number of days) of bleeding and/or spotting during various in- participation in the trial due to side effects of the treatment than
tervals throughout the one-month follow up period; however, the were women receiving placebo [RR 8.1, 95% CI 1.04, 63.40].
effect of EE treatment was inestimable, since standard deviations 2. Estrogen versus placebo (therapeutic treatment for DMPA
were not published. The Diaz 1990 study reported mean and total users; n= 1 study)
numbers of bleeding and spotting days during all treatment in- Only one of the included studies (Said 1996) was designed to
tervals throughout the entire year and did not separate individual evaluate the effects of an estrogen on bleeding irregularities in
treatment intervals. Women receiving estradiol reported shorter women using DMPA for family planning. This was one of the
episodes of bleeding and spotting throughout the year and fewer largest included studies, having randomised 278 DMPA users with
days of bleeding and spotting. However, it is not clear how many irregular bleeding to receive either EE 50 µg, oestrone sulfate 2.5
treatment cycles were included in the analysis. But it is reported mg or placebo for 14 days. This study was also designed to report
that the mean number of treatments per year per treated sub- on both short- and long-term success, with follow-up at 14 days
ject ranged from 2.2 to 3.1, with no differences between groups. (the duration of the treatment) and 12-18 months; unfortunately,
Witjaksono 1996 reported on the number of bleeding or spotting there was a high rate of discontinuation (over 40% in each group),
days and episodes in 90-day reference periods prior to and follow- giving the study a high risk of bias.
ing the treatment, and the number of bleeding or spotting days Ethinyl Estradiol was effective in stopping bleeding during treat-
per episode. The study results from the individual trials generally ment [RR 0.26, 95%CI 0.11, 0.60] and to a lesser extent after
suggest that the estrogen treatment had a beneficial effect in stop- three months [RR 0.06, 95%CI 0.00, 1.00] . Oestrone sulphate
ping bleeding. Two of the included studies (Alvarez-Sanchez 1996 was ineffective in stopping bleeding during treatment [RR 1.03,
and Boonkasemsanti 1996) reported the number of women who 95%CI 0.41, 2.59] and after three months.
experienced irregular bleeding during treatment; according to our The authors reported discontinuations and their causes among the
combined analysis, the use of estrogen reduced irregular bleeding study participants who presented at the study centres. But due to
during the treatment interval [RR 0.43, 95% CI 0.30-0.61 ). In the high numbers of study participants who were lost to follow-
addition, the Alvarez-Sanchez 1996 data support the conclusion up and who dropped out of the study prematurely, without giving
that women receiving EE report a lower incidence of unaccept- a reason, it was impossible to determine the true discontinuation
able bleeding patterns after treatment, as defined by the length of rates, particularly as related to bleeding irregularities and side ef-
the post-treatment bleeding-free interval. Fewer women reported fects, respectively.
a bleeding-free interval of less than 11 days after receiving the oral 3. Estrogen versus placebo (prophylactic treatment for DMPA
EE regimen than after receiving placebo [RR 0.28, 95% CI 0.14 users; n= 4 studies)
,0.58]. In contrast, no differences in the number of bleeding and/ Four studies were identified in which estrogen was administered

to new acceptors of DMPA, with the goal of preventing or re- regular bleeding during treatment, when compared with placebo
ducing bleeding irregularities. Two of these (El-Habashy 1970 [RR 0.08, 95% CI 0.03, 0.24] and reduced unacceptable bleeding
and Parker 1980) examined the effects of orally administered es- after treatment (as defined by the number of women experiencing
trogens, diethylstilbestrol (DES) and quinesterol, respectively, the bleed-free intervals of less than 11 days) [RR 0.02, 95% CI 0.00,
third (Goldberg 2002) evaluated the effects of a 17-beta estradiol- 0.29].
containing transdermal patch and the most recent study evalu- Witjaksono 1996 did not report discontinuations or side effects
ated the use of a vaginal ring releasing estradiol acetate (Dempsey in the study results; (Alvarez-Sanchez 1996) reported that the dis-
2010). continuation of Norplant due to bleeding disturbances was not
Two of the studies reported efficacy of the treatment in terms that significantly different between women in the combined hormone
could be incorporated into the present analysis. El-Habashy 1970 treatment and placebo groups, which was supported by our analy-
reported that women administered DES 1 mg daily exhibited more sis [RR 0.33, 95% CI 0.01, 7.99]. Discontinuation due to the side
acceptable bleeding patterns (defined as bleeding episodes of less effects of the treatment did not differ between groups; however,
than 8 days) than women receiving placebo [RR 0.45, 95% CI our analysis of the Alvarez-Sanchez data revealed a higher inci-
0.21, 0.96]. The trial of the vaginal ring (Dempsey 2010) reported dence of reported side effects (nausea or gastralgia) in the treat-
that the mean number of days of bleeding during treatment was ment group than in the placebo group [RR 7.16, 95% CI 1.72,
reduced in women using the ring; however this finding was not 29.71].
statistically significant, with a weighted mean difference of -8.30 6. Combined estrogen and progestin versus placebo (thera-
days in the treatment group (95% CI -20.2, 3.6). Parker 1980 peutic treatment for DMPA users; n= 1 study)
reported the percent of women with acceptable bleeding patterns One small trial (Sadeghi-Bazargani 2006 ) recruited DMPA users
in terms of numbers of bleeding episodes throughout 3-month who had cessation of menstruation for two months. Twenty four
intervals, following either one or three doses of quinestrol per women received low dose combined oral contraceptives (COCs)
DMPA injection segment (12 weeks). The primary outcome of and 22 received placebo. Significantly fewer women in the treat-
the (Goldberg 2002) study was DMPA continuation rates and ment group than in the placebo group continued to experience
(Dempsey 2010 also reported on this outcome. The combined amenorrhea [RR 0.38, 95% CI 0.19, 0.73]. The number of
analysis demonstrated that estrogen treatment is ineffective as a women who discontinued use of DMPA was less in the group
means to improve DMPA continuation [RR 1.00, 95% CI 0.78, assigned to receive low dose pills [RR 0.60, 95% CI 0.40, 0.88].
1.28]. Three of the studies in this category suffered from very high 7. Progestin versus placebo (therapeutic treatment for LNG
discontinuation and non-compliance rates, in both treatment and subcutaneous implant users; n= 1 study)
placebo groups One study (Diaz 1990) evaluated the effect of administering
4. Estrogen versus placebo (therapeutic treatment for minipill an additional progestin to Norplant users experiencing bleeding
users; n= 1 study) episodes of eight or more days. These women received 0.03 mg lev-
One small (n=12) study (Johannisson 1982) was designed to eval- onorgestrel tablets, twice a day for 20 days, starting on the eighth
uate the effects of estrogen treatment on bleeding irregularities consecutive day of bleeding. Women could treat extended bleed-
experienced by minipill (300 µg norethisterone) users. The bleeding up to five times in the year-long study. The authors described
ing data could not be used in the current analysis, as confidence a significant decrease in the total number of bleeding days and
intervals, rather than standard deviations, were presented in the bleeding and spotting days over the entire year in women who ever
descriptions of bleeding during the treatment interval. used the levonorgestrel, compared with those who ever used the
5. Combined estrogen and progestin versus placebo (thera- placebo, even when the untreated bleeding cycles were included in
peutic treatment for LNG subcutaneous implant users; n= 2 the analysis; however, the numbers of women in the final analysis
studies) were small (21 per group).
There were two studies (Alvarez-Sanchez 1996; Witjaksono 1996) Three of the 47 women enrolled in the levonorgestrel group elected
in which a combination of oral ethinyl estradiol and oral lev- to have their Norplant system removed, though none for reasons
onorgestrel was tested as a means to treat bleeding irregularities in related to bleeding; only one woman in the placebo group asked
Norplant users. The two studies together randomised 66 women to discontinue the contraceptive method [RR 2.94, 95% CI 0.32,
to receive the treatment regimen and 64 to receive placebo; of these 27.21].
61 and 60, respectively, were included in the analyses. As above, 8. Antiprogestin versus placebo (therapeutic treatment for
Alvarez-Sanchez 1996 reported efficacy in terms of the percentage LNG subcutaneous implant users; n= 1 study)
of women who experienced a cessation of bleeding within 3 days One of the included studies (Cheng 2000) was designed to evalu-
of treatment; the Witjaksono 1996 paper reported the number of ate the effects of the anti-progestin mifepristone on bleeding irreg-
bleeding days and episodes in 90-day reference periods. According ularities experienced by users of levonorgestrel-containing subder-
to the reports of the author and to our analyses, in the former mal contraceptive implants equivalent to Norplant. The study re-
study, the combined approach significantly reduced continued ir- sults stated that the women treated with mifepristone reported sig-

nificantly shorter episodes of bleeding during the treatment than 50 mg mifepristone, taken orally every 14 days, can lessen bleeding
prior to the study; however, both the treatment and control groups irregularities in new users of DMPA, in terms of percent days with
demonstrated a decrease in the frequency of bleeding in the one breakthrough bleeding and percent cycles with bleeding intervals
year of follow up. In the current analysis, we found no significant of more than 8 days.
difference between the groups with respect to the number of days 12. Antiprogestin versus placebo (prophylactic treatment for
of bleeding during treatment when reported 3 months after study minipill users; n= 1 study)
initiation; at 6 months, however, women using the anti-progestin In one study (Gemzell-Danielsson 2002), 103 women were ran-
reported fewer days of bleeding than did those receiving placebo domised to take either 150 mg of a novel antiprogestogen (Org
[WMD -8.00, 95% CI -12.41, -3.59]. No difference in the num- 31710) or placebo tablets once every 28 days, for a maximum of
ber of days of bleeding after the treatment was noted. No women seven treatment cycles. Although the study authors report an im-
in either group discontinued the use of the contraceptive method provement in the bleeding patterns of women who received the
due to bleeding irregularities. There was a significant effect of antiprogestin, our analysis did not reveal any differences between
mifepristone to decrease patient dissatisfaction with the treatment groups in terms of efficacy, discontinuation of the contraceptive
[RR 0.46; 95% CI 0.23, 0.91]. method due to bleeding irregularities or side effects, or the inci-
9. Antiprogestin versus placebo (prophylactic treatment for dence of side effects or adverse events.
LNG subcutaneous implant users; n= 1 study) 13. Combined antiprogestin and estrogen versus placebo
A single study (Massai 2004) was designed to evaluate the effect (therapeutic treatment for Implanon users; n= 1 study)
of two subsequent daily oral doses of 100 mg mifepristone in pre- One pilot study (Weisberg 2006) and a larger follow-on trial
venting bleeding irregularities in new users of Norplant. Of the (Weisberg 2009) randomised women using Implanon and expe-
120 women enrolled, 116 completed 6 months of treatment and riencing bleeding irregularities to take either mifepristone 50 mg
115 were included in the analysis. The mean number of bleeding for one day, followed by EE 20 µg/day for four days, or placebo
or spotting days during the course of the 180 days of the treatment for five days. The efficacy results were presented in a way not suit-
period of the trial was significantly lower in women who had taken able for our analysis but the authors reported in both trials that
mifepristone for 2 days at 30 day intervals than in women given mifepristone followed by EE was significantly more effective than
placebo [WMD -18.0; 95% CI -26.93, -9.07]. However, the im- placebo in stopping an episode of bleeding. Data extracted from
provement in bleeding patterns did not continue past the time of the more recent trialWeisberg 2009 reflect the number of women
discontinuation of treatment and, by 6 months after treatment, who experienced continued irregular bleeding during treatment;
there were no differences in reported acceptable bleeding patterns none of the 40 women randomized to receive the active treatment
between the two groups. None of the women in the treatment reported continued bleeding, compared with 11 of the 37 women
group discontinued use of Norplant for continued irregular bleed- who received placebo [RR 0.04, 95% CI 0.00, 0.66]. The analysis
ing. Of importance, one woman who received the anti-progestin of the pilot study demonstrated no significant differences between
did become pregnant during the course of the study. Two women the two groups of women in reporting any side effects [RR 1.22,
in the placebo group elected to have their implants removed due 95% CI 0.84, 1.75]. The 2009 trial reported no difference between
to continued irregular bleeding. This difference was not found to treatment groups with respect to the number of women who ex-
be significant, nor was the difference between groups with respect perienced headache; a combined analysis of both trials revealed no
to discontinuation from the study due to side effects of the treat- effect of treatment group on the number of women experiencing
ments, in the current analysis. nausea or vomiting [RR 0.5, 95% CI 0.18, 1.38]. The more recent
10. Antiprogestin versus placebo (therapeutic treatment for trial reported on discontinuation of the contraceptive method at
Implanon users; n=1 study) 90 and 180 days following initiation of treatment. Treatment with
One pilot study (Weisberg 2006) randomised women who used mifepristone followed by EE did not result in a favourable effect
Implanon implant and had bleeding irregularities to receive on method continuation rates at either time point.
mifepristone (25 mg twice/day for one day) then placebo for four 14. Venotonic versus placebo (therapeutic treatment for
days or placebo only for five days. The authors reported that minipill users; n= 1 study)
mifepristone alone was similar to placebo in stopping an episode In one of the included studies (Monteil-Seurin 1985), women us-
of bleeding. Unfortunately, the results were presented in a way ing a norethisterone acetate-containing minipill and complaining
not suitable for our analysis. A similar proportion of women in of bleeding irregularities were administered either a capillary pro-
both groups reported any side effect [0.93, 95% CI 0.61, 1.42] tecting venotonic drug (registered in France as Cyclo 3, contain-
or, specifically, nausea and vomiting [0.64, 95% CI 0.23, 1.80]. ing extract of Ruscus aculeatus with ascorbic acid and hesperidin
methyl chalcone) or placebo. The treatment schedule was cyclic,
11. Antiprogestin versus placebo (prophylactic treatment for with drug exposure for 20 continuous days, followed by a drug-
DMPA users; n= 1 study) free period during the expected time of menses. The mean number
Results of one small study (Jain 2003) suggest that a single tablet of of bleeding days during treatment was lower in the group using the

venotonic drug in comparison to the placebo group [WMD -2.0, treatment [WMD -5.6; 95% CI -10.04, -1.16]. The percentage
CI -2.78, -1.22]. This was the only one of the included studies that of women with unacceptable bleeding after treatment was signif-
attempted to quantify the amount of blood lost during treatment, icantly less in the treated group as reported by both( Kaewrudee
as a listed endpoint, and the study authors indicated that women 1999 and Buasang 2009 )and confirmed in the present combined
who received the Cyclo 3 needed less menstrual protection than analysis [RR 0.38; 95% CI 0.25, 0.6]. In the d’Arcangues 2004
did women in the placebo group. There were no study drop outs trial, the median duration of bleeding/spotting episodes after treat-
reported and no data were presented on side effects due to the ment and the median lengths of the bleed-free intervals were not
treatment. According to the study authors, treated women subjec- significantly different in the drug and placebo groups, as reported
tively reported less discomfort due to bleeding after 3 treatment by the authors. Archer et al (Archer 2008) reported the main study
cycles than did women who received placebo. outcomes as being the mean duration (number of days) of bleed-
15. Vitamin E versus placebo (therapeutic treatment for LNG ing and/or spotting during various intervals throughout the one-
subcutaneous implant users; n= 2 studies) month follow up period; however, the effect of ibuprofen treat-
Two of the included studies (d’Arcangues 2004 and Subakir 2000) ment was inestimable, since standard deviations were not pub-
were conducted to evaluate the effectiveness of vitamin E, 200 lished. No differences in the number of bleeding and/or spotting
mg/day for 10 days, in the treatment of bleeding irregularities ex- days within the 25 days following a five-day ibuprofen treatment
perienced by women using Norplant implants. In Subakir study, period were reported by these authors.
the mean number of bleeding days after the first treatment cy- In the Diaz 1990 trial none of the women receiving ibuprofen
cle was significantly less among the 38 women taking vitamin requested removal of the Norplant system, while one woman in
E than among the 34 women assigned to the placebo group the placebo group requested removal, though not for bleeding-
[WMD -4.4, CI -5.02, -3.78]. However, in the second, larger associated reasons. No differences in discontinuation rates or in-
study (d’Arcangues 2004), with more than 100 women in each cidence of side effects (headache and gastrointestinal upset) were
group, there were no statistically significant differences between noted in the single studies or in the combined analyses (where
the groups in terms of the length of bleeding/spotting episodes combinations were feasible). Patient dissatisfaction with treatment
and the length of bleeding-free intervals that followed cessation of was significantly lower as reported by Jadelle users taking celecoxib
bleeding. d’Arcangues 2004 reported median numbers of days of for bleeding irregularities, in comparison with the placebo group
bleeding, rather than means, given the non-normal distribution (Buasang 2009) [RR 0.29; 95% CI 0.11, 0.72].
of the data. In this study, discontinuation rates were high but did 17. Combined non-steroidal anti-inflammatory drug and vi-
not differ between groups, nor did the incidence of side effects. tamin E versus placebo (therapeutic treatment for LNG sub-
16. Non-steroidal anti-inflammatory drug versus placebo cutaneous implant users; n= 1 study)
(therapeutic treatment for LNG subcutaneous implant users; In the large study reported in d’Arcangues 2004, over 120 women
n=5 studies) using Norplant were randomly assigned to receive a combination
Five of the included studies (Archer 2008, Buasang 2009, of aspirin and vitamin E, while the same number received placebo.
d’Arcangues 2004, Diaz 1990 and Kaewrudee 1999) were de- The efficacy data were reported as medians, and no benefit of the
signed to evaluate the effects of non-steroidal anti-inflammatory treatment was demonstrated in the original analysis. In addition,
drugs (NSAIDS) on bleeding irregularities experienced by women our analyses indicated that there were no differences between the
using LNG-releasing sub-cutaneous implants (either Norplant or groups with respect to study discontinuation or side effects related
Jadelle). The regimens included oral ibuprofen 800 mg, three to the treatment .
times/day for five days (Diaz 1990); oral ibuprofen 800 mg, two 18. Non-steroidal anti-inflammatory drugs versus placebo
times/day for five days (Archer 2008); oral mefenamic acid 500 (therapeutic treatment for DMPA users; n= 2 studies)
mg, twice daily for 5 days (Kaewrudee 1999); and oral aspirin, 80 Two trials (Tantiwattanakul 2004 and Nathirojanakun 2006) eval-
mg/day for 10 days (d’Arcangues 2004) and celecoxib 200 mg/ uating the therapeutic effect of an NSAID on bleeding patterns
day for five days (Buasang 2009). in women using DMPA were included in the analysis. In the first,
The earliest paper reported that women taking ibuprofen experi- women were randomised to receive mefenamic acid (n=23) or
enced a decrease in the mean number of bleeding days after ini- placebo (n=25). In the second trial, 46 women were randomised
tiating treatment in all treated bleeding intervals over the course to receive either valdecoxib or placebo. . In a combined analy-
of a year and fewer bleeding and spotting days during the year sis, fewer women receiving NSAID treatment continued bleeding
(Diaz 1990). Of data from Kaewrudee and Buasang , 14 of the during or just after the treatment period, versus in the placebo
54 women taking an NSAID continued to experience irregular group [RR 0.42; 95% CI 0.25, 0.72]. In the first trial gastroin-
bleeding during the treatment, compared with 44 of 53 women testinal discomfort was reported by six women in the treatment
in the placebo group [RR 0.32; 95% CI 0.2, 0.51]. In addition, group and by none in the control group; this difference was not
Kaewrudee et al reported that women randomized to the mefe- found to be significant in our analysis. In the second trial no ad-
namic acid group experienced fewer days of bleeding during the verse effects were reported.

19. Selective estrogen receptor modulator versus placebo (ther- CI 0.26, 3.64] and [RR 0.76; 95% CI 0.31, 1.84], respectively.
apeutic treatment for LNG subcutaneous implant users; n= 1 There were no differences in the reporting of any side effects be-
study) tween the two groups [RR 0.83, 95% CI 0.53, 1.29]. The side
Abdel-Aleem 2005 was the only included trial to examine the ef- effect of nausea/vomiting was reported in both trials; a combined
ficacy of a selective estrogen receptor modulator (SERM), in this analysis demonstrated no benefit of the treatment, though results
case tamoxifen, on bleeding irregularities experienced by women were inconsistent between the studies. In the 2009 trial, fewer
using progestin-only methods of fertility regulation. The study women reported headache in the treatment group; however, this
was limited to women using Norplant. women received tamox- finding was not significant.The authors reported that there was
ifen, 10 mg tablets twice daily for 10 days or placebo. Women good compliance with treatment intake, with only 10% of study
randomised to the treatment arm were significantly less likely to participants reporting having missed any tablet.
experience irregular bleeding during treatment [RR 0.41; 95% CI .
0.21, 0.80] or unacceptable bleeding after treatment [RR 0.38; 22. Matrix metalloproteinase inhibitor versus placebo (thera-
95% CI 0.18, 0.88] or to discontinue the use of Norplant for any peutic treatment for DMPA users; n=1 study)
reason [RR 0.20; 95% CI 0.05, 0.87]. The effect of the SERM In a recently published trial (Abdel-Aleem 2012), 68 women using
in reducing Norplant discontinuation for bleeding-related reasons DMPA who experienced prolonged or frequent bleeding and/or
bordered on significance [RR 0.22; 95% CI 0.05, 0.98]. Women spotting patterns were randomised to receive doxycycline 100 mg/
receiving tamoxifen were more likely to report satisfaction with twice daily or an identical placebo, for five days. Trial participants
their treatment regimen [RR 0.22; 95% CI 0.11, 0.45] and were were followed for three months after the initial treatment to com-
no more likely to report side effects. pare patterns of bleeding and spotting. When compared with a
20. Antifibrinolytic versus placebo (therapeutic treatment for placebo, doxycycline treatment showed no benefit in stopping an
LNG subcutaneous implant users; n= 1 study) episode of bleeding within 10 days of treatment (RR 0.88, 95%
One randomised trial (Phupong 2006) evaluated the effects of CI 0.64, 1.21). Moreover, during the follow-up of two cycles post
an antifibrinolytic agent on bleeding patterns in women using treatment, no differences in either the mean number of bleeding
Norplant and reporting irregular bleeding. Sixty-eight Norplant or spotting days recorded by study participants were observed.
users were enrolled; half received tranexamic acid 500 mg twice/ Two women in doxycycline arm (2/34) and three women taking
day for five days and the other half received similar placebo. The placebo (3/34) discontinued using DMPA during the trial (RR
percentage of women whose irregular bleeding stopped at 7 days 0.67, 95% CI 0.12, 3.74). Several women reported side effects
after the initiation of treatment was significantly higher in the due to their treatments: in the doxycycline arm, two women ex-
tranexamic acid group than the placebo group [RR 0.55, 95 % CI perienced nausea and one complained of diarrhoea; whereas one
0.32, 0.92]. The percentage of women with unacceptable bleeding woman who received placebo reported nausea.
by four weeks after the initiation of treatment was higher in the 23. Antifibrinolytic versus placebo (therapeutic treatment for
treatment group (41%) than in the control group (24%) [RR 1.75, DMPA users; n= 1 study)
95% CI 0.85, 3.62]. One randomized trial (Senthong 2009) evaluated the effects of
21. Matrix metalloproteinase inhibitor versus placebo (thera- tranexamic acid for treatment of irregular bleeding secondary to
peutic treatment for Implanon users; n= 2 studies) use of DMPA. One hundred women were enrolled and random-
In a pilot study (Weisberg 2006) and a larger follow-on trial ized to receive either tranexamic acid (1000 mg per day for five
(Weisberg 2009), Implanon users who experienced prolonged or days) or placebo, and were followed for four weeks after the initial
frequent bleeding patterns were randomised to receive doxycy- treatment. Current analysis of the study results showed that six
cline 100 mg/twice daily or similar placebo, for five days. Follow out of the 50 women who were assigned the treatment group, and
up was for a period of 90 days in the pilot study; the larger trial 45 of the 49 women in the placebo group, experienced continued
implemented a 90-day treatment period, then a 90 day follow- irregular bleeding during the first week of treatment [RR 0.13,
up period. In the earlier study, the authors reported that doxycy- 95% CI 0.06, 0.28]. There was also a significant effect of tranex-
cline was more effective than placebo in stopping an episode of amic acid on unacceptable bleeding after treatment; women in the
bleeding; this finding was not replicated in the larger trial. Data treatment group experienced fewer days of bleeding and spotting
extracted from the 2009 trial showed no treatment benefit with in the four week follow-up period [mean number of days: 5.7 ±
respect to continued irregular bleeding during treatment; 11 of 2.5 days vs 17.5 ± 7.2 days, respectively].
the 32 women randomized to receive the active treatment reported 24. Non-steroidal anti-inflammatory drug versus placebo
continued bleeding, compared with 11 of the 37 women who re- (therapeutic treatment for Implanon users; n= 1 study)
ceived placebo [RR 1.16, 95% CI 0.58, 2.3]. A single trial (Phaliwong 2004) evaluated the effects of mefenamic
At 90 and 180 days following initiation of treatment, there were acid for treatment of irregular bleeding secondary to use of Im-
no differences in Implanon discontinuation rates between women planon. Fifty women were enrolled and randomized to receive ei-
receiving doxycycline and those receiving placebo [RR 0.98; 95% ther 1500 mg mefenamic acid per day for five days or placebo.

They were followed for four weeks after the initial treatment. Eight treatment group were more likely to have discontinued use of a
out of 23 women who were assigned to the treatment group, and previous contraceptive method due to weight gain.
18 of the 23 women in the placebo group, experienced contin- There was no significant difference with regards to patient dissat-
ued irregular bleeding during the first week following initiation of isfaction with treatment, as implied by drug noncompliance. Fur-
treatment [RR 0.44, 95% CI 0.24, 0.81, current analysis]. Dura- ther reports of blood loss improvement did not differ between the
tion of bleeding and spotting during the 28 days of follow-up was two groups. Similar numbers of women in each group requested
reported by the authors to be significantly less among women tak- removal of their LNG IUS during the trial.
ing mefenamic acid compared with women assigned to the placebo 26. Vitamin C supplementation versus placebo (prophylactic
group [mean number of days: 10.5 days vs 16.8 days, respectively]; treatment for DMPA users; n= 1 study)
however, we were unable to estimate the mean difference in con- A single trial (Harel 2002) evaluated the effects of oral vitamin C
tinued irregular bleeding because the standard deviations were not supplementation on bleeding patterns among adolescents initiat-
published. ing DMPA use. Fifty-five adolescent girls (age 16 ± 1 years) were
Due to the small number of women enrolled in the trial, and wide randomly assigned to one of four groups (three treatment groups
confidence intervals surrounding the point estimate of effect, in and a placebo group); only one of the treatment groups was in-
the current analysis of the results, there were no observed differ- cluded as a possible prophylactic treatment for bleeding irregu-
ences in side effects experienced by women taking mefenamic acid larities, the other two treatment groups were not included in the
compared with placebo. Abdominal discomfort was reported by present analysis. The treatment group received 500 mg vitamin
three women in the treatment group, compared with none in the C plus placebo per day and the placebo group received 2 placebo
placebo group. Headache was reported by one woman in each tablets per day. Follow-up visits were scheduled at three and six
group and breast tenderness was experienced by two women in months after the initial injection. There was no significant dif-
the mefenamic acid group, but none in the placebo group. ference in the number of days of bleeding during the follow up
25. Antiprogestin versus placebo (prophylactic treatment for period experienced by women in the treatment group, versus the
LNG IUS users; n= 1 study) placebo.
One randomized trial (Warner 2010) evaluated the prophylactic 27. Antiprogestin and matrix metalloproteinase inhibitor ver-
effect of the use of an antiprogestin to reduce bleeding irregulari- sus placebo (therapeutic treatment for Implanon users; n= 1
ties among new users of the LNG IUS. 136 women were enrolled; study)
69 were randomized to receive CDB-2914 (150 mg per day for In a single trial (Weisberg 2009), Implanon users who experienced
three days, starting on days 21, 49 and 77 after device insertion) prolonged or frequent bleeding patterns were randomised to re-
and 67 received placebo. Follow up visits were scheduled at 1, 3 ceive doxycycline 100 mg/twice daily for five days, with the ad-
and 6 months after device insertion. According to current anal- dition of 25 mg mifepristone on the first day, or similar placebo.
ysis,during the first 28 days following the initial treatment (i.e. The trial implemented a 90-day treatment period, with a 90 day
initiation on day 21 following LNG IUS insertion), there was a post-treatment follow-up period. Extracted data demonstrated a
significant difference in the percentage of days in which women significant treatment benefit with respect to continued irregular
experienced bleeding and/or spotting. Women taking anti-pro- bleeding during treatment; 1 of the 35 women randomized to re-
gestins reported, on average, bleeding and/or spotting on 46.7% ± ceive the active treatment reported continued bleeding, compared
20.6 days during the 28 day period, whereas women in the placebo with 11 of the 37 women who received placebo [RR 0.10; 95%
group recorded irregular bleeding on 57.3% ± 24.8 days during CI 0.01, 0.71].
the first 28-day cycle. However, any beneficial effect of treatment At 90 and 180 days following initiation of treatment, there were no
with this antiprogestin disappeared by the third treatment cycle differences in Implanon discontinuation rates between women re-
(i.e. the 28 days following initiation of treatment on day 77 af- ceiving doxycycline and mifepristone and those receiving placebo,
ter insertion). Women taking antiprogestin reported, on average, despite a tendency for improved continuation rates at 180 days in
bleeding and/or spotting on 38.2% ± 23.7 days during the 28 day the treatment group [RR 0.49; 95% CI 0.09, 2.52] and [RR 0.33;
period, whereas women in the placebo group recorded irregular 95% CI 0.09, 1.11], respectively.
bleeding on 28.7% ± 20.7 days during the third 28 day cycle. In The side effect of nausea/vomiting was reported slightly more fre-
fact, women in the placebo group reported a significantly lower quently by women in the treatment group; however, this difference
percentage of days of bleeding and/or spotting during the third was not significant. Alternatively, fewer women in the treatment
cycle. group reported headaches; again, this finding was not significant.
Twenty-three percent (14/61) of women taking CDB-2914 re- 28. Estrogen and matrix metalloproteinase inhibitor versus
ported a tendency to gain weight during the trial, compared with placebo (therapeutic treatment for Implanon users; n= 1 study)
only 4% (2/25) of women in the control group. While this dif- In a single trial (Weisberg 2009), Implanon users who experienced
ference is statistically significant, according to patient character- prolonged or frequent bleeding patterns were randomised to re-
istics collected at baseline, women who were randomized to the ceive doxycycline 100 mg/twice daily combined with EE 20 µg/

day for five days, or similar placebo. The trial implemented a 90- tinued the use of the LNG-IUS due to dissatisfaction with the de-
day treatment period, with a subsequent 90 day follow-up period. mands of the trial (patch arm) and IUS expulsion (placebo arm).
Extracted data demonstrated no treatment benefit with respect One woman in the patch group discontinued her treatment due
to the number of women reporting continued irregular bleeding to headache complaints. A greater proportion of women in the
during treatment; 14 of the 35 women randomized to receive the estradiol patch arm reported dissatisfaction with their treatment
active treatment reported continued bleeding, compared with 11 compared with the placebo group both at 4 weeks (39.5% versus
of the 37 women who received placebo [RR 1.35; 95% CI 0.71, 11.6%, p-value=0.01) and 12 weeks follow-up (13.5% versus 0).
2.55]. 30. Non-steroidal anti-inflammatory drug versus placebo
At 90 and 180 days following initiation of treatment, there were (prophylactic treatment for LNG IUS users; n= 1 study)
no differences in Implanon discontinuation rates between women A recently published trial (Madden 2012) evaluated the prophy-
receiving doxycycline and EE and those receiving placebo. lactic effect of naproxen in decreasing bleeding and spotting irreg-
The number of women reporting the side effects of nausea/vom- ularities among new users of the LNG IUS. The trial enrolled 129
iting or headache was not different between treatment groups. new users of the LNG IUS, and randomly assigned them to three
29. Estrogen versus placebo (prophylactic treatment for LNG arms for twelve weeks of treatment (84 days). Forty-two women
IUS users; n= 1 study) were assigned to receive naproxen (500 gm), 43 women received
One recently published trial (Madden 2012) evaluated whether a placebo identical to naproxen, and 44 women were assigned to
the application of a transdermal 0.1 mg estradiol patch decreased a transdermal estradiol arm. Comparisons between the estradiol
bleeding and spotting among new users of the LNG IUS. Over- patch and the placebo arms are presented and analysed elsewhere
all, the trial enrolled 129 women initiating the use of the LNG in this review.
IUS and randomly assigned them to three arms for twelve weeks Beginning the day after IUS insertion, the naproxen and placebo
of treatment (84 days). Forty-four women were assigned to the group took their 500 gm study medication twice daily for the first
transdermal estradiol arm, 42 women received a 500 gm NSAID, five days of each four week period during the 12 weeks of treat-
and 43 women received a placebo identical to the NSAID. Com- ment. Trial participants were asked to complete study diaries to
parisons between the NSAID and placebo arms are presented and record the occurrence of bleeding and spotting as well as com-
analysed elsewhere in this review. pliance with the study’s protocol. Telephone follow-up was con-
Women assigned to the transdermal estradiol group applied their ducted at 4, 8 and 16 weeks, and an in-person follow-up visit was
patch the day following IUS insertion and used it continuously, scheduled at 12 weeks.
changing the patch on a weekly basis, for the 12 week treatment Because the results were presented as means, range and quartiles,
period. Beginning the day after IUS insertion, the placebo group current analysis could not be done per review methodology. The
took their study medication twice daily for the first five days of authors reported that over the entire treatment period, women who
each four week period during the 12 weeks of treatment. Trial received naproxen reported fewer bleeding/spotting days than the
participants were asked to complete study diaries to record the placebo group [median and range: 27.5 days (5-83 days) naproxen
occurrence of bleeding and spotting as well as compliance with arm versus 32 days (9-84 days) placebo arm], however the differ-
the study’s protocol. Telephone follow-up was conducted at 4, 8 ence was not statistically different (p-value = 0.1). The distribu-
and 16 weeks, and an in-person follow-up visit was scheduled at tion of bleeding and spotting over the 12-week treatment period
12 weeks. showed that women taking naproxen were more likely to experi-
Because the results were reported as medians , range and quartiles, ence patterns of bleeding/spotting within the lowest quartile (i.e.,
current analysis could not be done , and the results presented as 2-21 days) compared with women who received placebo (42.9%
reported by the authors.During the entire treatment period of the versus 16.3 %). During the four week post-treatment period, there
trial, women using the estradiol patch reported a greater number were no reported differences in bleeding/spotting between women
bleeding/spotting days than the placebo group [median and range: in either group.
44 days (2-82 days) for estradiol patch arm versus 32 days (9-84 Over the 12 week treatment period, two women who received
days) for placebo arm], however the difference was not statisti- naproxen discontinued use of the LNG IUS due to pregnancy and
cally different (p-value = 0.15). The distribution of bleeding and chest pain. A woman in the placebo group discontinued using her
spotting over the 12-week treatment period showed that women LNG-IUS due to IUS expulsion. Reports of dissatisfaction with
in the estradiol patch arm were significantly more likely to ex- treatment differed minimally between the naproxen or placebo
perience patterns of bleeding/spotting within the highest quartile groups at 4 weeks (9.5% versus 11.6%); however, more women
(i.e., 54-84 days) compared with women who received placebo taking naproxen were dissatisfied with the treatment at 12 weeks
(40.9% versus 18.l %, p-value = 0.02). During the four week post- (11.4% versus 0).
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 discon-

DISCUSSION not be accepted by a large proportion of women.In the recent trial
of Madden(Madden 2012)A greater proportion of women in the
In performing the original review it became clear that clinical trial
estradiol patch arm reported dissatisfaction with their treatment
authors reported efficacy outcomes in such divergent manners so
compared with the placebo group both at 4 weeks (39.5% versus
as to make comparison of the outcomes across studies difficult or
11.6%, p-value=0.01) and 12 weeks follow-up (13.5% versus 0).,
impossible; this remains the case at the time of this update. Due
to the methodological differences among trials, very few could be Combined oral contraceptives (ethinyl estradiol and lev-
combined in our analysis; therefore our findings primarily describe onorgestrel) were used to treat bleeding irregularities among Nor-
the results from analyses of individual studies. Data for some of plant users in two trials, with the rationale being that most family
the outcomes selected for the review were difficult to extract or planning service delivery facilities would have such a therapy read-
interpret. In many studies discontinuation of the contraceptive ily available (Alvarez-Sanchez 1996 and Witjaksono 1996). The
method for bleeding reasons was not differentiated from discon- two studies reported a beneficial effect of treatment in stopping
tinuation for other reasons. And, finally, the numbers of women bleeding, though the endpoints and data in the latter study were
in many of the trials were small, making the results difficult to reported in such a way as to make incorporation in our analysis
interpret. impossible. We might presume to conclude that the addition of
a progestin to the treatment regimen offered no benefit over and
Several of the included studies were designed to evaluate the
above the effects of an estrogen alone, but that it did not compro-
effects of estrogen administration on bleeding irregularities as-
mise the safety or effectiveness of an estrogen-only therapy. One
sociated with Norplant or DMPA use. Estrogens may enhance
study evaluated the role of combined oral contraceptives in treating
those mechanisms that cause bleeding to cease, i.e. coagulation
amenorrhea associated with the use of DMPA (Sadeghi-Bazargani
or tissue repair (Shaaban 1984 and Viegas 1988). Results were
2006 ). These investigators reported that more women resumed
inconsistent, with ethinyl estradiol showing beneficial effects in
menstruation with the use of this therapy, and fewer women dis-
stopping a current bleeding episode as reported in several of the
continued the use of DMPA in comparison to placebo; these pos-
studies, and significant improvements in a combined analysis
itive results were confirmed in the present analysis. However, it is
of two trials among Norplant users (Alvarez-Sanchez 1996 and
difficult to draw any conclusion about this regimen as the type,
Boonkasemsanti 1996). According to Said (Said 1996), among
dose and duration of use of the combined oral contraceptive was
DMPA users, intake of ethinyl estradiol stopped bleeding better
not reported; in addition, the sample size was small, with fewer
than placebo during the treatment period; however, part of the
than 25 women in each study group.
data was reported as medians and therefore could not be incor-
porated into our analyses. The higher rates of study discontinua- The use of an additional progestin to resolve bleeding irregular-
tion related to side effects of estrogenic compounds (Diaz 1990, ities in Norplant users met with limited success in a single study
Alvarez-Sanchez 1996) should encourage providers to exercise cau- (Diaz 1990). While the study reported moderate improvements in
tion in recommending these regimens to their patients with bleed- bleeding in women using levonorgestrel compared with placebo, it
ing irregularities, particularly those with known sensitivity to es- suffered from high discontinuation rates, high rates of non-use of
trogens. the treatment, even when required by the protocol, and other po-
It is difficult to draw any firm conclusions from the data re- tential sources of bias. Because of the natural changes in bleeding
lated to the prophylactic use of estrogens to prevent bleeding ir- patterns over the first year of Norplant use, the data describing the
regularities in DMPA users. While the first of the three stud- overall mean number of bleeding days in every treated bleeding
ies (El-Habashy 1970) demonstrated a reduction in unacceptable interval (up to five in the year, but with a mean range of 2.2 to
bleeding during treatment with diethylstilbestrol, the study in- 3.1 treated cycles per woman per year) could not be included in
cluded only small numbers of women and was found to be of our analyses. We could not compare these mean data with data on
only moderate quality, due to possible inadequacies in allocation single intervals of treatment.
concealment and outcome assessment binding. In fact, all of the An anti-progestin (mifepristone) was used to treat bleeding
trials in this category suffer from weaknesses in design or imple- among Norplant users in one trial (Cheng 2000). According to
mentation, with high rates of discontinuations (23-38%) in two our analysis, users of mifepristone reported a significant decrease
of the trials (Parker 1980 and Goldberg 2002, respectively). In two in bleeding during treatment at six months following initiation of
of the trials (El-Habashy 1970 and Parker 1980) therapies were treatment, but not before. This supports the authors’ report that
tested that are no longer available for clinical use. The high rates all women experienced a decrease in the frequency of bleeding
of discontinuation and of non-compliance with the study proto- over the course of the one-year study, but that the decrease was
col in the Goldberg study (Goldberg 2002) not only confuse the more gradual in the placebo group than for those women receiving
interpretation of the results so that they could not be incorporated mifepristone.
into the present analysis, they also suggest that the tested therapy
(transdermal estrogen delivered by means of a daily patch) would Anti-progestins have also been shown to be somewhat promising

in the prevention of bleeding irregularities in DMPA (Jain 2003), produced in larger studies, possibly demonstrating a overestima-
minipill (Gemzell-Danielsson 2002 ), Norplant (Massai 2004) tion of the beneficial effects of drugs in small studies. Vitamin
and LNG IUS users (Warner 2010). In the first two studies, the E, for example, was effective in reducing the number of bleed-
authors reported that women taking antiprogestins reported fewer ing days during treatment in a pilot study conducted in Indone-
cycles with extended periods (more than 14 days) of breakthrough sia (Subakir 2000); these results were not replicated in a large
bleeding or better cycle control, respectively, than did placebo multi-centre study of the same regimen, even in the same In-
users; however, these outcomes were not identified for the present donesian centre (d’Arcangues 2004). The d’Arcangues et al study
review, and therefore the data could not be included in this analy- (d’Arcangues 2004) also failed to demonstrate the positive results
sis. Massai et al (Massai 2004) demonstrated acute, but not long- of NSAIDs on bleeding patterns reported by Diaz et al (Diaz
term, improvements in bleeding patterns in new Norplant users 1990), Kaewrudee et al (Kaewrudee 1999) , Nathirojanakun et
taking mifepristone.Warner 2010 reported similar results with the al (Nathirojanakun 2006) and Madden (Madden 2012). These
use of antiprogestin(CDB-2914) to reduce bleeding irregularities different results may be related to the use of different treatments
among new users of the LNG IUS. In contrast, mifepristone was - the studies that reported a positive effect of the treatment tested
not effective in stopping an episode of bleeding in women using ibuprofen, as used by 21 women (Diaz 1990), mefenamic acid,
Implanon (Weisberg 2006). In this trial, the addition of an estro- in 34 women (Kaewrudee 1999) or the COX-2 inhibitor, valde-
gen to mifepristone was more effective than placebo in stopping coxib, in 22 women (Nathirojanakun 2006); and naproxen in 42
an episode of bleeding. The data were presented in terms of 90- new users of LNG IUS. In the larger trial, in which an NSAID
day reference periods, before and after the treatment; our analysis was not effective, over 100 women who received aspirin were in-
was not able to capture the data presented in this manner. cluded in the analysis. On the other hand, the rationale for testing
both Vitamin E and NSAIDs is scientifically compelling. As the
Glasier et al (Glasier 2002) and Jain et al (Jain 2003) have sug- angiogenic response in the endometrium of Norplant users has
gested that mifepristone may functionally inhibit progesterone, been found to be lower than in women with normal menstrual
leading to up-regulation of endometrial estrogen receptors and a cycles (Subakir 2000), the disturbance in the angiogenic process,
positive effect on bleeding patterns similar to exogenous estro- as well as an imbalance of pro- and antioxidant processes in the
gen treatment. In contrast, Grow and co-workers (Grow 1998) endometrium, may contribute to irregular bleeding in Norplant
have demonstrated, primarily in non-human primates, that even users. Supplementation with vitamin E may serve as an effective
though estrogen receptors are increased following mifepristone ex- method of preventing membrane damage caused by oxygen radi-
posure, the receptors may not be transcriptionally active. cals (Halliwell 1992) or of increasing endometrial angiogenic ac-
While anti-progestins have been shown in some trials to improve tivity(Subakir 2000 ).
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 One small study have suggested that the antifibrinolytic com-
to be established, as the approach to antagonize the effect of the pound, tranexamic acid, can have a short-term therapeutic ef-
contraceptive progestin to achieve better bleeding patterns may fect on bleeding disturbances in Norplant users (Phupong 2006)
potentially compromise the efficacy of the contraceptive method. .Tranexamic acid has been used around the world for over 20
In fact, one pregnancy was reported in the trial using the highest years to treat heavy menstrual bleeding. Tranexamic acid, a syn-
dose of mifepristone (Massai 2004). thetic lysine derivative, is an antifibrinolytic drug that prevents
the breakdown of fibrin by competitively blocking binding sites
The results of the single trial that was designed to evaluate the of plasminogen.By slowing the process of dissolving the tiny clots
effects of a SERM (tamoxifen) on bleeding patterns in women that are formed as a result of bleeding, tranexamic acid can re-
using progestin-only contraceptive methods were quite promising duce the amount of bleeding (Lukes 2011). Small studies eval-
in terms of effectiveness, safety, continuation of the contracep- uated the effect of the matrix metalloproteinase inhibitor, doxy-
tive method and compliance with treatment (Abdel-Aleem 2005). cycline (DOX), in terminating an episode of prolonged bleeding
This was the only regimen that demonstrated an effect that lasted in Implanon users. One pilot study showed a beneficial effect of
longer than the period of treatment. Again, this result needs to DOX (Weisberg 2006). But these results were not replicated in a
be substantiated in larger trials, with longer periods of follow-up, trial done in the same centre(Weisberg 2009) and in a more recent
before any clinical recommendation can be made. Grow et al hy- trial testing DOX to treat bleeding episodes among DMPA users
pothesized that SERMs may improve bleeding patterns disrupted (Abdel-Aleem 2012).The three trials used the same dose and reg-
by the use of progestin-only contraceptives by antagonizing the imen of DOX.
angiogenic effect of estrogen (Grow 1998).
Several other types of treatments have been shown to be some-

what effective in small trials, but the results have not been re- AUTHORS’ CONCLUSIONS

Implications for practice widely utilized, studies could be more easily and effectively inter-
preted and compared, and the findings would more readily make
Based on the results of this review, women may benefit to a de-
their way into evidence-based practice, as appropriate. It is rec-
gree from the interventions described, particularly with regard to
ommended that future studies attempt to collect data on blood
cessation of an ongoing bleeding episode. Several regimens offer
loss using objective and validated measurement tools, such as the
promise in regulating bleeding in the short term, but positive re-
pictorial blood assessment scores.
sults need to be reproduced in larger scale trials. The results of
the review do not support the routine clinical use of any of the Through the process of performing the review, it became clear to
treatment or preventive regimens to exert anything other than a the authors that additional research directed towards the possible
short-term effect on the current bleeding episode; no medium- or underlying mechanisms of bleeding among users of these prod-
long-term beneficial effects were described in any of the studies. ucts is required. Results from such studies would not only help
The review was focused on pharmacologic interventions; however, to further identify potential therapeutic interventions, but would
it is acknowledged that proper counseling at the time of method help to ensure that clinical studies and, eventually, treatments can
initiation can help to prepare women for the bleeding irregulari- be based on etiological findings.
ties that they may experience and improves method continuation
rates.
Implications for research ACKNOWLEDGEMENTS

Many women using progestin-only methods experience unaccept- The statistical advice and assistance of Barts J.A. Mertens, De-
able bleeding disturbances, discontinue use, and are left without partment of Medical Statistics, Leiden University, the Netherlands
contraceptive protection or switch to a less effective method. It and Dr Gilda Piaggio, UNDP/UNFPA/WHO/World Bank Spe-
is essential that the family planning research community develop cial Programme of Research, Development and Research Training
standardized methodologies for research and reporting in this field in Human Reproduction are gratefully acknowledged, for their
of study. If a common set of outcomes could be developed and contributions to the original review.
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without intermenstrual bleeding during contraception with Hadisaputra W, Kazi A, Ramos RM, d’Arcangues C,
300 mcg Norethisterone (NET) Minipill. Contraception Belsey EM, Noonan E, Olayinka I, Pinol A, World
1982;25:13–30. Health Organization, Special Programme of Research,
Kaewrudee 1999 {published data only} Development and Research Training in Human
Kaewrudee S, Taneepanichskul S, Jaisamraun U, Reproduction, Task Force on Long-acting Systemic
Reinprayoon D. The effect of mefenamic acid on controlling Agents For Fertility Regulation. Clinical evaluation of the
irregular uterine bleeding secondary to Norplant use. therapeutic effectiveness of ethinyl oestradiol and oestrone
Contraception 1999;60:25–30. sulphate on prolonged bleeding in women using depot
medroxyprogesterone acetate for contraception. Human
Madden 2012 {published data only}
Reproduction 1996;11:1–13. [: PMID 8982739]
Madden T, Proehl S, Allsworth JE, Secura GM, Peipert JE.
. Naproxen or estradiol for bleeding and spotting with the Senthong 2009 {published data only}
levonorgestrel intrauterine system: a randomized controlled Senthong A, Taneepanichskul S. The effect of Tranexamic
trial. American Journal of Obstetrics & Gynecology 2012;206 acid for treatment irregular uterine bleeding secondary to
(2):129.e 1-8. DMPA use. J Med Assoc Thai 2009;92:461–5.
Massai 2004 {published data only} Subakir 2000 {published data only}
Massai MR, Pavez MR, Fuentealba B, Croxatto H, Subakir SB, Setiadi E, Affandi B, Pringgoutomo, Freisleben
d’Arcangues C. Effect of intermittent treatment with HJ. Benefits of vitamin E supplementation to Norplant
users - in vitro and in vivo studies. Toxicology 2000;148: Sapire 1991 {published data only}
173–8. [: ISBN 3–928624–98–9] Sapire KE. A study of bleeding patterns with two injectable
Tantiwattanakul 2004 {published data only} contraceptives given postpartum and the effect of two non-
Tantiwattanakul P, Taneepanichskul S. Effect of mefenamic hormonal treatments. Advances in Contraception 1991;7:
acid on controlling irregular uterine bleeding in DMPA 379–387.
users. Contraception 2004;70:277–279.
Additional references
Warner 2010 {published data only}
Warner P, Guttinger A, Glasier AF, Lee RJ, Nickerson Adeyemi 2012
S, Brenner RM, Crtichley HOD. Randomized placebo- Adeyemi, A. S, D. A. Adekanle. Progestogen-only
controlled trial of CDB-2914 in new users of a injectable contraceptive: experience of women in Osogbo,
levonorgestrel-releasing intrauterine system shows only southwestern Nigeria. Ann Afr Med 2012;11:27–31.
short-lived amelioration of unscheduled bleeding. Human
Affandi 1998
Reproduction 2010;25:345–53.
Affandi B. An integrated analysis of vaginal bleeding
Weisberg 2006 {published data only} patterns in clinical trials of Implanon. Contraception 1998;
Weisberg E, Hickey M, Palmer D, O’Connor V, Salamonsen 58:99s–107s.
L, Findlay JK, Fraser IS. A pilot study to assess the effect of d’Arcangues 1992
three short-term treatments on frequent and/or prolonged d’Arcangues C, Odlind V, Fraser IS. Dysfunctional uterine
bleeding compared to placebo in women using Implanon. bleeding induced by exogenous hormones. In: Alexander
Human Reproduction 2006;21:295-302. NJ, d’Arcangues C editor(s). Steroid hormones and uterine
Weisberg 2009 {published data only} bleeding. Washington: AAAS Press, 1992:81–105. [: ISBN
Weisberg E, Hickey M, Plamer D, O’Connor V, Salamonsen 0–87168–508–6]
LA, Findlay JK, Fraser IS. A randomized controlled trial Datey 1995
of treatment options for troublesome uterine bleeding in Datey S, Gaur LN, Saxena BN. Vaginal bleeding patterns
Implanon users. Human Reproduction 2009;24:1852–1861. of women using different contraceptive methods (implants,
Witjaksono 1996 {published data only} injectables, IUDs, oral pills) - an Indian experience. An
Witjaksono J, Lau TM, Affandi B, Rogers PA. Oestrogen ICMR Task Force Study. Indian Council of Medical
treatment for increased bleeding in Norplant users: Research. Contraception 1995;51:155–165. [MEDLINE:
preliminary results. Human Reproduction 1996;11: PMID 7621684 UI 95347181]
109–114. Fan 1996
References to studies excluded from this review Fan M, Sujuan G. Menstrual bleeding patterns in Chinese
women using the Norplant subdermal implant. Human
Archer 1996 {published data only} Reproduction 1996;11:14–19.
Archer DF, Philput CA, Weber ME. Management of Fraser 1983
irregular uterine bleeding and spotting associated with Fraser IS. A survey of different approaches to management
Norplant. Human Reproduction 1996;11:24–30. of menstrual disturbances in women using injectable
Cseffalvay 1965 {published data only} contraceptives. Contraception 1983;28:385–397.
Cseffalvay T, Klose S. (Estrogen-gestagen therapy with Fraser 1998
hormonally induced uterine bleeding.11.Therapeutic use of Fraser IS, Tiitinen A, Affandi B, Brache V, Croxatto H,
Klimovan). Deutsche gesundheitswesen 1965;20:1334–1339. Diaz S, Ginsburg J, Gu S, Holma P, Johansson E, Meirik O,
d’Arcangues 2000 {published data only} Mishell DR Jr, Nash HA, von Schoultz B, Sivin I. Norplant
d’Arcangues C. Management of vaginal bleeding consensus statement and background review. Contraception
irregularities induced by progestin-only contraceptives. 1998;57:1–9. [: PMID 9554244]
Human Reproduction 2000;15:24–29. Grow 1998
Glasier 2002 {published data only} Grow DR, Reece MT, Hsiu JG, Adams L, Newcomb
Glasier AF, Wang H, Davie JE, Kelly RW, Critchley HO. PM, Williams RF, Hodgen GD. Chronic antiprogestin
Administration of antiprogesterone up-regulates estrogen therapy produces a stable atrophic endometrium with
receptors in the endometrium of women using norplant: a decreased fibroplast growth factor: a 1-year primate study in
pilot study. Fertility and Sterility 2002;77:366–372. contraception and amenorrhea. Fertility and Sterility 1998;
Piya-Anant 1998 {published data only} 69(5):936–943. [: PMID 9591506]
Piya-Anant M, Koetsawang S, Patrasupapong N, Dinchuen Halliwell 1992
P, d’Arcangues C, Piaggio G, Pinol A. Effectiveness of Halliwell B, Gutteridge JM, Cross CE. Free radical,
cyclofem in the treatment of depot medroxyprogesterone antioxidants and human disease: where are we now?.
acetate induced amenorrhea. Contraception 1998;57(1): Journal of Laboratory and Clinical Medicine 1992;119:
23–28. 598–620.

Lukes 2011 clinical trial of depot-medroxyprogesterone acetate given
Lukes AS, Kouides PA, Moore KA. Tranexamic acid: a three-monthly at doses of 100 mg or 150 mg: II. The
novel oral formulation for the treatment of heavy menstrual comparison of bleeding patterns. Contraception 1987;35:
bleeding. Womens Health (Lond Engl). 2011;7(2):151–8. 591–610. [: PMID 2959448]
Newton 1994 Shaaban 1984

Newton JR, d’Arcangues C, Hall PE. A review of “once- Shaaban MM, Elwan SI, el-Kabsh MY, Farghaly SA,
a-month” combined injectable contraceptives. Journal of Thabet N. Effect of levonorgestrel contraceptive implants,
Obstetrics and Gynaecology 1994;4:S1–S34. Norplant, on blood coagulation. Contraception 1984;30:
421–430. [: PMID 6440738]
Nutley 1997 Suvisaari 1996
Nutley T, Dunson TR. Treatment of bleeding problems Suvisaari J, Lahteenmaki P. Detailed analysis of menstrual
associated with progestin-only contraceptives: survey bleeding patterns after postmenstrual and postabortion
results. Advances in Contraception 1997;13:419–428. insertion of a copper IUD or a levonorgestrel-releasing
Said 1987 intrauterine system. Contraception 1996;54:201–208.
Said S, Omar K, Koetsawang S, Kiriwat O, Srisatayapan Y, Viegas 1988
Kazi A, Ajmal F, Wynter HH, Pretnar-Darovec A, Benitez Viegas OA, Singh K, Koh S, Singh P, Ratnam SS. The effects
IB, World Health Organization, Task Force on Long-Acting of Norplant on clinical chemistry in Singaporean acceptors
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Reproduction. A multicentered phase III comparative ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Abdel-Aleem 2005
Methods Randomized trial

Study duration: 3 months
Type of trial: parallel
Outcome assessment blinding: yes
Drop outs: 7 (7%)
Validity criteria: A
Participants 100 women in the first year of Norplant use, complaining of increased bleeding
Age:
Tamoxifen: 32.48 ± 5.6
Pl: 32.28 ± 6.1
Education level:
Tamoxifen: 26/50 illiterate; 24/50 some education
Pl: 24/50 illiterate; 26/50 some education
Setting: Family planning clinic, university hospital
Diagnostic criteria:
Abnormal/increased bleeding defined as current episode of bleeding/spotting longer than
8 days OR bleeding-free interval less than 15 days
Interventions Agents:
Tamoxifen (n=50): 10 mg twice a day, for 10 days, oral;
Placebo (n=50): twice a day, for 10 days, oral.
Treatment length: 10 days
Follow up: 3 months
Outcomes Percent of women who stopped bleeding during the treatment:

Overall, within 3 days, within 7 days, within 10 days.
Bleeding, spotting or bleeding/spotting days during follow up:
First month, second month, third month
Bleed-free interval post-treatment (days)
B/S episodes in 90 day reference period
Discontinuation of contraceptive method due to bleeding
Discontinuation of treatment due to lack of improvement
Side effects related to treatment:
Headache, GI disturbance, dizziness, fatigue, hot flush, other
Patient satisfaction with treatment, over time:
First month, second month, third month - data not given (no difference between groups)
Notes
Risk of bias
Bias Authors’ judgement Support for judgement

Abdel-Aleem 2005 (Continued)
Allocation concealment (selection bias) Low risk A - Adequate
Blinding (performance bias and detection Low risk A - Adequate

bias)
All outcomes
Drop outs (%) > 10 Low risk A - Adequate
Abdel-Aleem 2012

Study duration: three months
Drop outs: 5/34 (14.7%) .Doxycyclin 8.9%, Control 5.9%
Validity criteria: B (moderate risk of bias)
Participants 68 women using DMPA as a contraception for at least one month and having bleed-
ing episode,defined as [≥8 bleeding or spotting days or bleeding-free interval less
than15days) and were expected to be able to keep an accurate menstrual diary. Lactating
women were excluded for fear of the effect of DOX on the breast fed infant.Women
who had been diagnosed to have any local gynecological abnormality or those who were
receiving any other treatment for bleeding within the last 1month prior to the study
were also excluded
Setting: family planning clinic in a University Hospital
Age:DOX 29.6±7.3 years .Placebo 30.0±5.7
Interventions Doxycyclin (DOX) 100 mg capsules PO/ twice daily for 5 days.
Placebo one capsule PO/ twice daily for 5 days.
Outcomes The primary outcome of the study was the cessation of the current bleeding episode
within 10 days.Other outcome measures included the number of days needed to stop a
current episode of bleeding,the length of the next bleeding-free intervals,uterine bleeding
patterns in the 3 months after
treatment, women’s satisfaction with the treatment,side effects encountered during treat-
ment and discontinuation of theDMPA and its reason
Notes
Risk of bias
Allocation concealment (selection bias) Low risk closed sealed envelopes
Blinding (performance bias and detection Low risk Double blinded

bias)
All outcomes

Abdel-Aleem 2012 (Continued)
Drop outs (%) > 10 High risk 14.7 %
Alvarez-Sanchez 1996

Study duration: 8 weeks
Outcome assessment blinding: inadequate
Drop outs: 16 (10.66%)
Validity criteria: C (High risk of bias)
Participants 150 Norplant users in the first year of use enrolled; 134 included in analysis
Age (years):
EE (n=43) 23±4.2
LNG+EE (n=45): 24.6±3.8
Pl (n=46): 25.0±4.5
Setting: Family planning clinic
Prolonged bleeding: (bleeding or spotting 8 days or more)
Irregular bleeding (bleeding-free interval <15 days)
Interventions EE: 50 mcg/day x 20 days, orally;

LNG: 250 mcg/day + EE 50 mcg/day x 20 days orally;
Pl: 1/day x 20 days, orally
Follow-up 8 weeks
Outcomes Effectiveness of treatment, as measured by a cessation of B/S in 3 days of treatment or

less
Mean number of bleeding days during treatment interval
Percentage of women with bleeding-free interval of 20 days or more
Percentage of women with bleeding-free interval of less than 11 days
Discontinuation of contraceptive method because of bleeding
Side-effects related to treatment (stomach pain, nausea)
Discontinuation rate because of side-effects
Notes
Risk of bias
Allocation concealment (selection bias) Unclear risk B - Unclear
Blinding (performance bias and detection High risk C - inadequate

bias)
All outcomes

Alvarez-Sanchez 1996 (Continued)
Drop outs (%) > 10 High risk C - Drop out rate 10.66%
Archer 2008

Study duration: 30 days
Outcome assessment blinding: adequate
Drop outs: 1 (1/107)
Validity criteria: A (low risk of bias)
Participants 107 women using LNG subcutaneous implant for more than one month
Age (years):
EE (n=20) not mentioned
IBU (n=42): not mentioned
Pl (n=44): not mentioned
Setting: Five university hospital Ob/Gyn departments in the United States of America
Bleeding or spotting lasting 8 or more consecutive days
S/B for more than 10 days out of 14 days within the preceding three weeks
Interventions EE: 20 mcg/day x 10 days, orally; with 5 days IBU Pl given twice a day.
IBU: 800 mg/ twice a day x 5 days, with 10 days of a daily EE Pl orally;
Pl: 1/day x 10 days orally and the other taken twice/day x five days orally.
Follow-up 30 days
Outcomes The number of days of bleeding and/or spotting during treatment

The number of days of bleeding and/or spotting within the first 30 days following
treatment
Notes The dose of IBU administered is described inconsistently in the publication; dose has
been confirmed with first author
Risk of bias

bias)
All outcomes

Boonkasemsanti 1996

Drop-outs: 0
Participants 64 Norplant users in the first year of use.

Age (years):
Estradiol patch (E) 27±3;
Pl 25±4.
Setting: University Ob/Gyn Department, Bangkok, Thailand
Bleeding problems as defined by bleeding more than 8 days, and/or bleeding-free interval
less than 10 days
Estradiol patch (n=33) releasing 100 mcg/24 hours x 6 weeks;
Pl patch (n=31) x 6 weeks.
Follow-up: 6 weeks
Outcomes “Clinical improvement” refers to women with an initially abnormal pattern, who develop
a normal pattern (bleeding less than 8 days and/or bleeding free interval more than 20
days
Continued irregular bleeding
Notes
Risk of bias

bias)
All outcomes

Buasang 2009

Drop-outs: 0
Participants 40 women using Jadelle for 9-13 months.

Age (years):
Celecoxib 34.1±7.4
Placebo 29.5±9.8
Setting: Family planning clinic, university hospital, Bangkok, Thailand
Diagnostic criteria:Bleeding problems as defined by bleeding/spotting more than 8 days,
or current bleeding episode initiated after a bleeding-free interval less than 14 days
Celecoxib (n=20) 200 mg/day x 5 days, oral;
Pl (n=20) 1/day x 5 days, oral.
Follow-up: 28 days
Outcomes Percent of women who stopped bleeding during the treatment (within 7 days)
The length of bleeding-free interval in 28 days.
The number of bleeding days after initial treatment.
Patient satisfaction with treatment.
Notes
Risk of bias
Allocation concealment (selection bias) Low risk A - Adequate. Celecoxib and placebo were
packed in opaque sealed envelopes with la-
beled number

bias)
All outcomes

Cheng 2000

Drop-outs: 0
Participants 100 women using Norplant for 3-43 months.

Age (years):
Mifepristone 29.5;
Placebo 30
Frequent vaginal bleeding, defined as bleeding episode occurring more often than once
every 24 days
Mifepristone (n=50) 50 mg (2x25 mg tablets) once, orally.
Pl (n=50) 2 tablets once, orally.
Treatment started on the third day after the start of a B/S episode.
After the first treatment, women were given a date to return to the clinic once/28 days
for 5 months (a total of 6 treatments in all)
Follow-up: 12 months
Reference period 1: 90 days before the first treatment;
Reference periods 2 and 3 cover 180 days from the first treatment, and together include
6 treatment months and the first 12 days of the seventh month.
Reference period 4 started 39 days after the last treatment and ended 90 days later
Outcomes Number of bleeding days over time:

Reference period 1, reference period 2, reference period 3, reference period 4
Average duration of bleeding episodes (days):
Reference period 1, after treatment
Women rating their treatment as satisfactory
Discontinuation rate because of bleeding
Side effects related to treatment
Notes
Risk of bias

bias)
All outcomes

d’Arcangues 2004

Study duration: 1 year, with follow up at end of treatment, 3 months and 6 months
Drop outs:
Total: 139/486 (28.6%)
Aspirin: 30/122 (25%);
Vitamin E: 38/120 (32%);
Combined aspirin and vitamin E: 40/121 (33%);
Pl: 31/123 (25%).
Validity criteria: C (high risk of bias)
Participants 486 women in the first 6 months of Norplant use

347 women completed the study
Age: all groups: 29.0 ± 5.0
Setting: Developing country research institutes, University Ob/Gyn department; family
planning clinic
Prolonged bleeding: 8 or more days;
Clinically important bleeding patterns in 90-day reference period:
Amenorrhea: no bleeding
Infrequent: fewer than 2 B/S episodes in ref. pd
Frequent: more than 4 B/S episodes in ref pd
Irregular: a range of lengths of bleeding-free intervals greater than 17 days
Prolonged: at least one B/S episode lasting more than 10 days
Aspirin 80 mg/day x 10 days, orally
Vitamin E 200 mg/day x 10 days, orally
Combined aspirin + vitamin E x 10 days, orally
Pl x 10 days, orally
Treatment length: 10 days; repeated up to 5 times in year, if 20 days have passed between
treatment cycles
Follow up: 1 year, with visits after each treatment period and at 3 and 6 months
Outcomes Efficacy in management of 1-5 episodes of prolonged bleeding:

Number of B/S days in episode;
Number of B/S days from the first day of treatment;
Number of B/S days following the treatment episode.
Discontinuation of treatment due to side effects
Headache, GI discomfort
Patient dissatisfaction with treatment at 3 months:
Improved pattern, unchanged pattern, worse pattern, no answer/unknown
Notes
Risk of bias

d’Arcangues 2004 (Continued)

bias)
All outcomes
Drop outs (%) > 10 High risk C - High risk of bias(28.6%)
Dempsey 2010

Study duration: 6 months, with follow up at end of 3 months and 6 months
Outcome assessment blinding: No
Drop outs: At three months DMPA: 13/36 (36%), Vaginal ring: 9/35 (26%);
At 6 months: DMPA 20/36 (56%), Vaginal ring 18/35 (51%)
Participants 71 women who initiated DMPA

Age:
Untreated: n=14 of 36 randomized (39%) age 18-20 years; n=22 of 36 randomized
(61%) age 21 years or older
Vaginal ring: n=14 of 35 randomized (40%) age 18-20 years; n=21of 35 randomized
(60%) age 21 years or older
Setting: Family Planning Clinic in New York City, USA.
Inclusion criteria: at least 18 years old, had not used DMPA or Lng IUS in the preceding
120 days
Exclusion criteria: oligomenorrhoea (fewer than 4 periods in the last 6 months), amen-
orrhoea, or contraindications to either DMPA or estrogen
Education:
Untreated: n=11 of 36 randomized (31%) less than high school; n=25 of 36 randomized
(69%) high school or greater
Vaginal ring: n= 12 of 35 randomized (34%) less than high school; n=23 of 35 random-
ized (66%) high school or greater
Interventions Each participant received DMPA 150 mg IM injection for contraception

Estradiol vaginal ring (n=26 included in 3-month analysis): 24.8 mg of estradiol acetate
which releases ar a rate equivalent to 0.1 mg of estradiol per day for 3 months
Untreated controls (n=23 included in 3-month analysis): no placebo ring available
Outcomes Days of bleeding and spotting

Number of bleeding/spotting episodes
Discontinuation of the contraceptive method

Dempsey 2010 (Continued)
Side effects related to treatment (data not shown)

Patient satisfaction with treatment
Notes Several of the outcomes described above were stated outcomes of the trial; however, data
were not presented for all outcomes. For others, data were not disaggregated by treatment
group. Data extracted for the purposes of the current review included the number of
days of bleeding during treatment and discontinuation of the contraceptive method
Risk of bias
Allocation concealment (selection bias) Low risk A - adequate
Blinding (performance bias and detection High risk C - High risk of bias
bias)
All outcomes
Drop outs (%) > 10 High risk C - High risk of bias
Diaz 1990
Methods Quasi-randomized trial

Study duration:
one year
Type of trial:
Parallel
Outcome assessment blinding: Yes
Drop outs:
Total: 43/183 (24%)
LNG 13/47 (28%)
EE 12/45 (27%)
Ibuprofen 10/45 (22%)
Pl 8/46 (17%).

Age (years; mean ± SD):
LNG 26 ± 4;
EE 27 ± 4;
Ibuprofen 27 ± 4;
Pl 27 ± 4.
Frequent vaginal bleeding, defined as bleeding episode occurring more often than once
every 24 days

Diaz 1990 (Continued)
LNG 0.03 mg tablets, twice daily x 20 days, orally;
EE 0.05 mg tablets once daily x 20 days, orally;
Ibuprofen 800 mg, three times daily x 5 days, orally;
Pl once daily, x 20 days, orally.
Schedule:
Treatment began on the 8th consecutive day of each B/S episode, as needed throughout
the year, but no more than five treatments in the year.
Follow-up:
Each time a B/S episode lasted more than 7 days, and at three month intervals
Outcomes Mean number of bleeding days per woman in intervals of days 1-20, 1-5, and 6-20 of
treatment
Mean number of B/S days per woman in intervals of days 1-20, 1-5, and 6-20 of treatment
Mean number of B/S days per treated woman in the year:
DIscontinuation of contraceptive method because of lack of improvement at the end of
the year
Discontinuation of treatment due to side effects (gastric intolerance)
Notes
Risk of bias

bias)
All outcomes
El-Habashy 1970

Outcome assessment blinding: unclear
Drop-outs: 2/63 (3.2%)
validity criteria: B (moderate risk of bias)
Participants 63 post-partum women who chose DMPA as their method of contraception

Age: data not given
Setting: Hospital
Diagnostic criteria: Prophylactic prevention of bleeding problems. No definition of nor-
mal or abnormal bleeding patterns provided

El-Habashy 1970 (Continued)
Interventions Diethylstilbestrol (DES; n=32): 1mg tablet/daily x 90 days, orally;

Pl (n=31) 1 vitamin tablet/daily x 90 days.
Follow-up: monthly
Outcomes Number of women experiencing bleeding episodes of less than 8 days (including 0 days)
:
First month, second month, third month
Compliance, as defined as taking the agent 25 days/month or more:
Notes
Risk of bias
Blinding (performance bias and detection Unclear risk B - Unclear

bias)
All outcomes
Gemzell-Danielsson 2002

Study duration: 16-28 weeks
Drop-outs: 12/103 (12%)
Anti-progesterone: 3/52 (5.8%)
Placebo: 9/51(17.6%)
Participants 103 women using 75 mcg desogestrel pill daily

Age (mean):
Antiprogestogen 31.6;
Placebo 32.8
Setting: Research institutes
Diagnostic criteria, within a 90-day reference period:
Amenorrhea: no B/S
Infrequent bleeding: fewer than three B/S episodes, excluding amenorrhea
Frequent bleeding: more than five B/S episodes
Prolonged bleeding: one or more B/S episode lasting more than 14 days
Irregular bleeding: range of the length of bleeding-free intervals less than 17 days

Gemzell-Danielsson 2002 (Continued)
Org 31710 (antiprogesterone) 150 mg (three tablets x 50 mg), once/28 days, orally
Placebo three similar tablets, once/28 days, orally
Schedule: One dose every 28 days for a maximum of seven treatments.
Follow-up: 16-28 weeks.
Outcomes Effectiveness of treatment:

Number (percentage) of days with recorded B/S, cycle day 8-28:
Cycle 1, cycle 3, cycle 6
Number (percent) of subjects with B/S episodes starting day 8-28:
Cycle 1, cycle 3, cycle 6
Discontinuation rate because of bleeding
Side effects related to treatment (headache, emotional lability, acne, breast pain)
Discontinuation of the study because of side effects
Notes
Risk of bias

bias)
All outcomes
Drop outs (%) > 10 High risk C - High risk of bias, drop out rate 35%.
Goldberg 2002

Outcome assessment blinding: adequate
Drop-outs: 50/132 (38%)
Estradiol 30/66 (45%);
Pl: 20/66 (30%)
Participants 132 post-abortion DMPA users in the first year of use

Age (years):
Estradiol patch 24±5.2;
Pl 23±5.9.
Education: No significant difference between groups
Setting: Hospital-based research unit.

Goldberg 2002 (Continued)
Interventions Agents and schedule:

17-beta Estradiol patch (0.1 mg/day, brand name Climara)/weekly x 3 patches per month
(3 weeks on + 1 week off/month), transdermal.
Pl patch 1 patch/weekly x 3 patches per month (3 weeks on + 1 week off/month),
transdermal.
Duration of treatment: 3 months.
Follow-up: at months 4, 8 and 12.
Outcomes Effectiveness of treatment as defined by association between use of estrogen patches and
regular bleeding patterns, over time:
Discontinuation of the contraceptive method over time:
At 4 months, 8 months, 12 months
Discontinuation of the contraceptive method due to bleeding:
Non-compliance with treatment due to side effects (inconvenience and skin irritation):
(Compliance defined as using 6 out of 9 treatment patches)
Reasons for non-compliance
Side effects related to treatment (skin irritation, inconvenience)
Notes High rate of DMPA discontinuation.

High rate of non-compliance with the study protocol.
Risk of bias

bias)
All outcomes
Drop outs (%) > 10 High risk C - High risk of bias(38% drop out)
Harel 2002

Drop-outs: unclear
Validity criteria: B (Moderate risk of bias)
Participants 55 DMPA users

Age (years):
Vit C+Pl : 16+1
Pl :16±1.

Harel 2002 (Continued)
Setting: Hospital-based adolescent clinics in the United States
Interventions Group 1: Vit. C 500 mg plus Pl x daily, oral x 6 months

Group 2 : Control Pl 2 tab daily, oral x 6 months
Follow up: at 3 and 6 months
Outcomes Days of bleeding during the first interval (first 3 months)

Days of bleeding during second interval (months 4-6)
Discontinuation of the contraceptive method.
Notes Vitamin B6 was included as an intervention to prevent weight gain; however outcomes
related to bleeding were reported for the VitamIn B6 alone group. Because this was not
identified and tested as an intervention to affect bleeding, the results of the Vitamin B6
groups are not included in the analysis.
Risk of bias
Blinding (performance bias and detection Unclear risk B - Moderate risk of bias
bias)
All outcomes
Drop outs (%) > 10 Unclear risk B - Moderate risk of bias
Jain 2003

Study duration: 6 treatment cycles of 28 days each
Outcome assessment blinding: not clear
Drop-outs: 0
Participants 20 new users of DMPA

Age: not described
Setting: University Ob/Gyn department
Diagnostic criteria: not described
Mifepristone: 50 mg, every 14 days, orally
Pl: similar tablet every 14 days, orally
Treatment length: six cycles (6 x 28 days)
Follow-up: six cycles

Jain 2003 (Continued)
Outcomes Percent days with breakthrough bleeding (median)

Cycles 1-3, cycles 4-6, total cycles 1-6
Number (percent) cycles with bleeding intervals 8 or more days
Number (percent) cycles with bleeding intervals 14 or more days
Ovulation
Notes
Risk of bias

bias)
All outcomes
Johannisson 1982

Study duration: 4 months (1 month control + 3 months treatment)
Drop-outs: 0
Participants 12 minipill users (300 µg norethisterone (Net))

Age: 25-30 years
Setting: clinical research settings
Diagnostic criteria: Intermenstrual bleeding in second month of Net use

EE (n=6) 50 µg/daily x 7 days, orally.
Pl (n=6) once/daily x 7 days, orally.
Treatment started in case of intermenstrual bleeding, after endometrial biopsy.
Follow-up: 7 days.
Outcomes Number of days with bleeding during 7 days treatment
Notes
Risk of bias

Johannisson 1982 (Continued)

bias)
All outcomes
Kaewrudee 1999

Drop-outs: 2/69 (2.9%)
Participants 69 women using Norplant for 3-36 months recruited; 67 included in analysis..
Age (years):
Mefenamic acid (MEF n=34) 27.2±9.4;
Pl (n=33) 25.0±5.9.
Setting: Family planning clinic in hospital Ob/Gyn Department
Prolonged bleeding defined as 8 or more continuous days of bleeding or spotting;
Irregular bleeding defined as a current bleeding episode following a bleeding-free interval
of less than 15 days

MEF 500 mg/twice daily x 5 days, orally;
Pl 2 capsules/twice daily x 5 days, orally.
Follow-up: One and four weeks after treatment.
Outcomes Percentage of women who stopped bleeding within 7 days after initiation of treatment
Bleeding free interval more than 20 days at 28 days follow-up
Number of B/S days within the 28 day follow up period (Mean+SD)
Side effects related to treatment (headache, dysmenorrhea, breast tenderness and leuko-
rrhea)
Discontinuation rate due to side effects
Notes
Risk of bias

Kaewrudee 1999 (Continued)

bias)
All outcomes
Madden 2012

Outcome assessment blinding: two arms blinded from subjects and investigators
(naproxen and placebo); estradiol patch arm not blinded
Drop-outs: 23/129 = 17.8% overall. Differential loss within trial arms: placebo = 6/43
(14%); estradiol patch = 10/44 (23%); naproxen = 7/42 (17%)
Participants Number of subjects: 129 women randomised

Age: < 21 years: 11.4 (estradiol) 11.9 (naproxen) 9.3 (placebo)
21 - 29 years 68.2 (estradiol) 66.7 (naproxen) 69.8 (placebo)
≥ 30 years 20.5 (estradiol) 21.4 (naproxen) 20.9 (placebo)
Education level:
Some high school 25.6 (estradiol) 14.6 (naproxen) 14.6 (placebo)
High school 46.5 (estradiol) 56.1 (naproxen) 41.5 (placebo)
College/grad 27.9 (estradiol) 29.3 (naproxen) 43.9 (placebo)
BMI: <25 27.3 (estradiol) 35.7 (naproxen) 51.2 (placebo)
25-29.9 22.7 (estradiol) 35.7 (naproxen) 20.9 (placebo)
≥ 30 50 (estradiol) 29.3 (naproxen) 27.9 (placebo)
Diagnostic criteria used to define the condition of interest:
Bleeding = 1 panty liner, tampon, or pad/day
Spotting = < 1 panty liner, tampon or pad/day
Setting: University research clinic
Naproxen (N=42): 500 mg oral naproxen. Days 1-5, twice daily for 4 week period
starting the day after LNG-IUS insertion
Estradiol (N=44): 0.1 mg transdermal patch. Placed day after insertion, and used con-
tinuously, changing weekly.
Placebo (N=43): Identical pill to Naproxen. Days 1-5, twice daily for 4 week period
starting the day after LNG-IUS insertion
Treatment duration: 12 weeks
Outcomes Effectiveness of treatment (i.e., reduction in bleeding/spotting): median bleeding/spot-

ting days and range for entire treatment period
Discontinuation of the contraceptive method:
Discontinuation of treatment due to lack of improvement: Not reported
Discontinuation of treatment due to side effects:

Madden 2012 (Continued)
Patient dissatisfaction with treatment
Notes
Risk of bias
Allocation concealment (selection bias) Low risk A-Adequate
Blinding (performance bias and detection High risk C-one arm is not blinded
bias)
All outcomes
Drop outs (%) > 10 High risk C-drop out rate 17.8%
Massai 2004

Drop-outs: 5/120 (4%)
Participants 120 new Norplant users enrolled

116 completed 6 months of treatment
115 included in analysis
Age (Mean ± SD):
Mifepristone (n=58): 30.1 ± 4.1;
Pl (n=57): 28.3 ± 4.8.
Setting: Research institute
Prolonged bleeding episode: more than 8 consecutive days of B/S
Mifepristone 100 mg/day x 2 days at 30 day intervals, orally
Placebo: pill/day x 2 days at 30 day intervals, orally.
Treatment duration:
2 days, repeated at 30 day intervals for 6 months (months 2-7 of implant use)
Start 30 days after implant insertion.
Follow-up:
Monthly during treatment and for 6 additional months.
Additional follow up after treatment, for 6 months (total 13 months)
Outcomes The number of B/S days per woman during the 180-day treatment (Mean+SD), over
time;
At end of treatment, 6 months after end of treatment

Massai 2004 (Continued)
Number of bleeding episodes in treatment period:

Number (%) of women with 5-8 bleeding episodes during 6 months treatment, number
(%) of women with more than 8 bleeding episodes during treatment
Mean length of B/S episodes (days)
Women with 1 or more episode of prolonged bleeding, number (%), over time
At the end of treatment, 6 months after end of treatment
Total number B/S episodes
Number of prolonged bleeding episodes
Total number of B/S days at 6 months and post-treatment
Proportion of bleeding episodes that were prolonged
Mean length (days) of B/S episodes longer than 8 days
Discontinuation of the contraceptive method
Discontinuation of the contraceptive method due to bleeding
Side effects (headache, weight loss, acne, nervousness, abdominal pain, lichen sclerosus)
Notes
Risk of bias

bias)
All outcomes
Monteil-Seurin 1985

Outcome assessment blinding: no
Drop-outs: 0
Participants 40 Minipill (Norethisterone acetate - NET) users for at least one month
Age: average 25 years.
Setting: Clinical practice

Cyclo 3 (Capillary protecting venotonic drug containing Ruscus aculeatus) 4 capsules
daily x 20 days
Pl 4 capsules daily x 20 days
Duration: 20 days, stopped during menses, repeated for 3 months.

Monteil-Seurin 1985 (Continued)
Follow-up: 3 months.
Outcomes Duration of bleeding in intermenstrual bleeding episodes (days), over time:

Pre-treatment, at 1-month, at 3 cycles
Number of days pads or tampons used
Pre-treatment, at 1-month, at 3 cycles
Subjective assessment of discomfort caused by bleeding:
Pre-treatment, during treatment (after 1 cycle), after 3 cycles
Tolerance to drug
Notes
Risk of bias
Blinding (performance bias and detection High risk C - High risk of bias
bias)
All outcomes
Nathirojanakun 2006

Drop outs: 5/51 (9.8%)
Participants 51 DMPA users (3-12 months) reporting abnormal bleeding

Age (years):
Valdecoxib (n=25) 24.1 ± 6.6;
Pl (n=26) 25.1 ± 7.3.
Setting: Family planing clinic in hospital Ob/Gyn department
Diagnostic criteria: 8 or more days of bleeding or spotting prior to bleeding on the day
of admission

Valdecoxib (Cox-2 inhibitor): two tablets (20 mg /tablet) daily x 5 days, orally;
Pl 2 tablets daily x 5 days, orally.
Follow-up: 4 weeks.
Outcomes Number of treatment days required to stop bleeding

Percentage of women who stopped bleeding within 7 days following initiation of treat-

Nathirojanakun 2006 (Continued)
ment
Total number of bleeding-free days in 28 day follow-up period
Length of the bleeding-free interval in the 28 day follow up period
Notes
Risk of bias

bias)
All outcomes
Parker 1980

Drop-outs: 55/236 (23%).
Participants 236 women who used DMPA for 90 days;

214 women included in analysis.
Age: Varying from 24.0±3.84 to 26.0±5.43, with no differences between groups.
Setting: Clinic
Acceptable bleeding pattern: 2-4 bleeding episodes in a 12 week injection segment, with
no episode longer than 8 days;
Prolonged bleeding pattern: a bleeding episode longer than 8 days;
Amenorrhea: no bleeding;
Irregular bleeding: one bleeding episode or more than 4 bleeding episodes in a 12 week
injection segment
Interventions Agents.
Quinestrol (Quin) 400 ug, orally.
Placebo, orally
Doses:
One capsule Quin or Pl/injection segment;
Three capsules Quin or Pl/injection segment.
Regimens:
One capsule Quin of Pl with DMPA injection;
One capsule Quin or Pl two weeks after DMPA injection;

Parker 1980 (Continued)
One capsule Quin or Pl at 0, 4, and 8 weeks after DMPA injection (total 3 capsules);
One capsule Quin or Pl at 2, 6, and 10 weeks after DMPA injection (total 3 capsules)
Outcomes Acceptable bleeding, over time

First injection segment, all segments combined:
Discontinuation because of bleeding
Discontinuation because of amenorrhea
Discontinuation due to side effects (headache, weight change, palpitations, sickness)
Notes
Risk of bias

bias)
All outcomes
Drop outs (%) > 10 High risk C - High risk of bias(23 % drop out)
Phaliwong 2004

Drop-outs: 4/50 (8%).
Participants 50 Implanon users for at least two months

Age (Mean ± SD):
Mefenamic acid (n=23): 31.2 ± 5.1;
Pl (n=23): 28.6 ± 5.4.
Setting: Family Planning Clinic, Bangkok ,Thailand
Prolonged bleeding episode: more than 8 consecutive days of bleeding or spotting
Irregular bleeding defined as a current bleeding episode initiated after a bleeding-free
interval of <15 days
Interventions Mefenamic acid (250 mg /capsule): 500 mg x tds, oral x5 days

Pl two capsules x tds , oral x 5 days
Follow up: 1 and 4 weeks

Phaliwong 2004 (Continued)
Outcomes Days of treatment required for stopping the bleeding episode

Total number of bleeding/spotting days.
The length of bleeding free interval after the initial treatment
Notes
Risk of bias

bias)
All outcomes
Phupong 2006

Drop outs: 0
Participants 68 women using Norplant for 3-36 months and reporting irregular bleeding.
Age (years):
Tranexamic acid (n=34) 27.0 ± 5.7;
Pl (n=34) 29.1 ± 6.1
Setting: Family planning clinic in hospital Ob/Gyn Department
Bleeding or spotting for eight or more continuous days, or a current bleeding episode
initiated after a bleeding-free interval of 14 days or less

Tranexamic acid: two capsules (250 mg /capsule) 4 times daily x 5 days, orally;
Pl: two capsules 4 times daily x 5 days, orally
Follow up: one and four weeks
Outcomes Percentage of women who stopped bleeding after one week

Percentage of women who stopped bleeding after four weeks
Mean duration of bleeding/spotting days during 28 days of follow up
Notes

Phupong 2006 (Continued)
Risk of bias

bias)
All outcomes
Sadeghi-Bazargani 2006

Study duration: undefined
Drop outs: unclear
Participants 46 DMPA users with amenorrhea

Combined oral contraceptive: n = 24
Pl: n = 22
Age: not given for trial population.
Setting:
District Health centres.
Education: not given for trial population.
Diagnostic criteria: Amenorrhea as defined as two months without menstrual bleeding
following DMPA injection
Low dose combined oral contraceptives (components not reported), daily, orally.
Pl daily, orally.
Treatment duration: not reported
Follow up duration: not reported.
Outcomes Effectiveness of combined oral contraceptive in comparison to Pl in resolving amenor-

rhea.
Discontinuation of the contraceptive.
Notes
Risk of bias

Sadeghi-Bazargani 2006 (Continued)

bias)
All outcomes
Drop outs (%) > 10 Unclear risk B - Moderate risk of bias
Said 1996

Drop-outs:
Total: 117/278 (44%)
EE: 40/90 (44.4%);
Oestrone sulfate (OS): 37/91 (40.7%);
Pl: 40/97 (41.2%).
Participants 278 women using DMPA for <6 months

EE n=90, OS n=91, Pl n=97
Age:
EE 27.0±4.7;
OS 27.6±4.7;
Pl 27.0±4.9.
Settings: Hospitals, University Ob/Gyn Department, Research Institute, Family Plan-
ning Centre
Vaginal bleeding episode >7 days, during first or second injection interval;
Prolonged bleeding: a bleeding episode lasting 10 days or more;
Amenorrhea: no bleeding within a 90 day reference period;
Frequent bleeding: more than 4 bleeding episodes in a 90 day reference period;
Infrequent bleeding: fewer than 2 B/S episodes in a 90 day reference period;
Irregular bleeding: bleeding-free intervals greater than 17 days in a 90 day reference
period
EE (n=90) 50 µg/day x 14 days, orally.
OS (n=91) 2.5 mg/day x 14days, orally.
Pl (n=97) 1/day x 14 days, orally.
Follow-up
At the end of 14 days treatment (short-term success).
12 months follow-up (long-term success).

Said 1996 (Continued)
Outcomes Bleeding stopped during the 14 day treatment course, with at least 2 days bleed-free
interval
Continued irregular bleeding
Median time to cessation of bleeding and spotting (days)
The median number of B/S days during treatment
Number of B/S days in 90 day reference period after treatment (mean ± SD)
Number of B/S episodes in 90 day reference period following treatment
Discontinuation due to bleeding, at one year
Discontinuation due to amenorrhea, at one year
Discontinuation due to Oestrogen treatment failure, at one year
Notes
Risk of bias

bias)
All outcomes
Drop outs (%) > 10 High risk C - High risk of bias(44% drop out)
Senthong 2009

Drop-outs:
Total: 1/100
Participants 100 DMPA users for a period of 1-18 months, with abnormal bleeding
Age:
Tranx:29.6+7.0
PL :28.6+7.6
Setting:
Family planning clinic.
Diagnostic criteria:Bleeding problems as defined by bleeding/spotting more than 8 days,
or current bleeding episode initiated after a bleeding-free interval less than 14 days
Tranexamic acid tablets (n=50) , containing 250 mg/tablet x 4 times daily, oral x5 days;
Pl tablets (n=49) x 4 tablets daily, oral x5 days.
Follow-up: 28days

Senthong 2009 (Continued)
Outcomes Percent of women who stopped bleeding during the treatment:

( within 7 days).
The length of bleeding-free interval in the 28 days.
Notes
Risk of bias

bias)
All outcomes
Subakir 2000

Drop-outs: zero

Age: 18-40 years.
Setting: University
“Bleeding problems” presumably as reported by the study participants
Vitamin E (Vit) (n=38) 200 mg /day x 10 days, oral;
Pl (n=34) 1/day x 10 days, oral.
Treatment repeated 30 days from Day 1 of first treatment.
Follow-up: 2 months.
Outcomes Number of bleeding days before first treatment cycle

Number of bleeding days after first treatment cycle
Notes Diagnostic criteria are not reported.

No data given for second treatment cycle.
Risk of bias

Subakir 2000 (Continued)
Allocation concealment (selection bias) Unclear risk B - Unclear; Moderate risk of bias

bias)
All outcomes
Tantiwattanakul 2004

Dropouts: 6/54 (11%)
Validity criteria: B ( moderate risk of bias)
Participants 54 women using DMPA for 3-12 months enrolled

48 women in analysis
Age (Mean ± SD):
Mefenamic acid (MEF; n=23): 30 ± 6.8;
Pl (n=25): 27 ± 5.8.
Setting: Family planning clinic at hospital Ob/GYN department
Bleeding on day of admission, following 8 or more days of continuous B/S (Abnormal
bleeding)
Interventions Mefenamic acid (MEF) 500 mg twice daily x 5 days, orally;

Pl: capsules 2X/day x 5 days, orally.
Treatment duration: 5 days
Follow-up duration 1 and 4 weeks.
Outcomes Women who stopped bleeding within 7 days of initiation of treatment (number, percent)
Women who did not stop bleeding within 7 days of initiation of treatment
Mean bleed-free interval during 28 days following initiation of treatment (days)
Other outcomes listed, but no data reported:
Total number of days B/S
Number of days of treatment required to stop bleeding.
Notes No data reported for some of the listed outcomes.
Risk of bias

Tantiwattanakul 2004 (Continued)

bias)
All outcomes
Drop outs (%) > 10 High risk B -drop out 11%
Warner 2010

Dropouts: 20/136 (14.7%)
Validity criteria: B (moderate risk of bias) Drop out rate >10 %
Participants 136 new users of Levonorgestrel IUS

Age: Progesterone receptor modulator(PRM): 36.9+6.5
Placebo(PL): 35.8+7.0
Setting: Family Planning Clinic, University of Edinburgh,UK.
Inclusion criteria: women initiating the use of IUS, 19-49 years, regular menstruation
(17-42 days cycle),period <11 days
Exclusion criteria: breast feeding within three months ,chronic medical or psychiatric
disorder, gynaecological disorders, and long-term medications
Interventions PRM 50 mg/day for 3 days start at days 21,49,77 after LNG IUS insertion
PL the same schedule
Follow up: 6 months ( at 1,3 and 6 months) after LNG IUS
Outcomes Effectiveness of treatment

Patient dissatisfaction with treatment.
Blood loss during treatment
Notes
Risk of bias

bias)
All outcomes

Warner 2010 (Continued)
Drop outs (%) > 10 High risk C - moderate risk of bias(drop out 14.7%)
Weisberg 2006

Study duration: 180 days (90 days before and 90 days after treatment)
Drop outs: 17/179 (9.5%)
Participants 179 Implanon users

Age (years):
Mifepristone 29.9 ± 1.0;
Mifepristone+EE 27.6 ± 1.0;
Doxycycline 28.8 ± 1.0;
Pl 28.9 ± 1.0.
Setting: University women’s health research centres
Prolonged bleeding: B/S episode longer than 10 days in 90 day reference period (as per
WHO);
Frequent bleeding: more than 4 B/S episodes in 90 day reference period (as per WHO)

Mifepristone 25 mg twice daily x 1 day + Pl twice daily x 4 days, orally.
Mifepristone 25 mg twice daily x 1 day +EE 20 ug x 4 days, orally.
Doxycycline 100 mg twice daily x 5 days.
Placebo twice daily x 5 days.
Follow up: 90 days.
Outcomes Number of days of B/S following start of treatment.

Duration of the first B/S interval after treatment.
Mean number of B/S episodes in the 90 day reference period.
Mean duration of first B/S episode in the 90 day reference period post-treatment.
Total number of B/S days during the pre- and post-treatment 90 day reference periods.
Number of bleed-free days post-treatment.
Side effects.
Notes
Risk of bias

Weisberg 2006 (Continued)

bias)
All outcomes
Weisberg 2009

Study duration: 180 days (90 days treatment reference period and 90 days post- treat-
ment)
Drop outs: 25/179 (13.9%)
Validity criteria: B (moderate risk of bias), drop out rate > 10 %
Participants 204 Implanon users

Age (years):
Doxycycline: 28.6 ± 6.8;
Doxycycline+EE : 28.8+6.0
Mifepristone+EE : 29.1 ± 7.2;
Mifepristone+Doxycycline: 29.0 ± 6.0;
Pl 28.8 ± 5.8.
Education:
High school or more:
Doxy : 40/41
Doxy+EE: 40/41
Mifepristone+EE: 41/41
Mifepristone+Doxy: 41/42
Placebo: 38/40
Setting: University women’s health research centres in four sites at Australia
Prolonged bleeding: B/S episode longer than 10 days in 90 day reference period (as per
WHO);
Frequent bleeding: More than 4 B/S episodes in 90 day reference period (as per WHO

Doxycycline 100 mg twice daily x 5 days.
Doxycycline100 mg twice daily+ EE 20ug once daily x 5 days.
Placebo twice daily x 5 days.
Mifepristone 25 mg twice daily x 1 day + EE 20 ug once daily x4 days +Pl twice daily x
4 days, orally.
Mifepristone 25 mg twice daily x 1 day + Doxy 100 mg twice daily x 5 days, orally.
Follow up: 90 days.

Weisberg 2009 (Continued)
Outcomes Number of days of B/S following start of treatment.

The mean number of days of B/S immediately following treatment.
The duration (number of days) of the first B/S -free interval after the initiation of
treatment.
Mean number of days of B/S during the 90 day treatment reference period.
The mean number of B/S episodes during the 90 day treatment reference period
Side effects related to treatment
Notes
Risk of bias

bias)
All outcomes
Witjaksono 1996

Drop-outs: not given
Participants 91 women using Norplant for 3-12 months were recruited; 48 women included in
analysis
Age (mean ± SE):
EE: (n=18) 30.2 ± 2.6;
EE + LNG: (n=16) 29.5 ± 2.8;
Pl: (n=38) 29.3 ± 3.2.
Setting: University Obstetric and Gynecology departments
Prolonged bleeding, frequent bleeding, irregular bleeding as defined by WHO (1990)
EE 50 ug/day x 21 days, orally;
EE 30 ug/day + LNG 150 ug/day x 21 days, orally;
Pl daily/21 days, orally
Follow-up: 90 days.

Witjaksono 1996 (Continued)
Outcomes Number of B/S days in 90 day reference period pre-treatment (mean ± SD)
Number of B/S days in 90 day reference period post-treatment (mean ± SD)
Number of B/S episodes in 90 day reference period pre-treatment (mean ± SD)
Number of B/S episodes in 90 day reference period post-treatment (mean ± SD)
Number of B/S days per episode, pre-treatment (mean ± SD)
Number of B/S days per episode, post-treatment (mean ± SD)
Notes
Risk of bias
Allocation concealment (selection bias) High risk C - Inadequate

bias)
All outcomes
Drop outs (%) > 10 Unclear risk B - Unclear
EE - Ethinyl Estradiol
LNG - Levonorgestrel
NSAID - Nonsteroidal antiinflammatory drug
Pl - Placebo
B/S - Bleeding/Spotting
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Archer 1996 Interim data
Cseffalvay 1965 Non-randomized trial
d’Arcangues 2000 Review article
Glasier 2002 Non-randomized trial.
Piya-Anant 1998 Treatment involved switching contraceptive methods.
Sapire 1991 Unable to determine which treatment group results were associated with experimental and placebo intervention
- data blinded

DATA AND ANALYSES
Comparison 1. Estrogen vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Continued irregular bleeding 2 153 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.30, 0.61]
during treatment
2 Bleeding during treatment (days) 2 153 Mean Difference (IV, Fixed, 95% CI) -6.9 [-9.08, -4.72]
3 Unacceptable bleeding after 1 84 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.14, 0.58]
treatment
4 Discontinuation of contraceptive 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
method
4.1 Discontinuation of 1 91 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.01, 8.15]
contraceptive method
contraceptive method because
of bleeding
5 Discontinuation of treatment 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.99]
due to lack of improvement
due to side-effects
7 Side-effects related to treatment 1 89 Risk Ratio (M-H, Fixed, 95% CI) 9.09 [2.23, 37.06]
7.1 Nausea 1 89 Risk Ratio (M-H, Fixed, 95% CI) 9.09 [2.23, 37.06]
8 Bleeding/spotting after treatment 1 64 Mean Difference (IV, Fixed, 95% CI) -0.30 [-1.63, 1.03]
(# days)
Comparison 2. Estrogen vs placebo (DMPA/Therapeutic)
No. of No. of
1 Continued irregular bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
during treatment
1.1 Estradiol 1 187 Risk Ratio (M-H, Fixed, 95% CI) 0.26 [0.11, 0.60]
1.2 Estrone sulfate 1 188 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.69, 1.77]
after treatment(3 months).
2.1 Estradiol 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.06 [0.00, 1.00]
2.2 Estrone sulphate 1 144 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.41, 2.59]

Comparison 3. Estrogen vs placebo (DMPA/Prophylactic)
No. of No. of
1 Unacceptable bleeding during 1 61 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.21, 0.96]
treatment
2 Bleeding during treatment (days) 1 49 Mean Difference (IV, Fixed, 95% CI) -8.3 [-20.20, 3.60]
method
of bleeding
4 Non-compliance with treatment 1 132 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.93, 1.45]
Comparison 5. Estrogen and progestin vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
during treatment
treatment
4 Discontinuation of contraceptive 1 100 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.99]
method because of bleeding
due to side-effects
6.1 Nausea 1 91 Risk Ratio (M-H, Fixed, 95% CI) 7.16 [1.72, 29.71]
Comparison 6. Estrogen and progestin vs placebo (DMPA /Therapeutic for amenorrhea)
No. of No. of
1 Continued amenorrhea during 1 46 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.19, 0.73]
treatment
2 Discontinuation of the 1 46 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.40, 0.88]

Comparison 7. Progestin vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
method
Comparison 8. Antiprogestin vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
1.1 at 3 months 1 100 Mean Difference (IV, Fixed, 95% CI) -4.0 [-9.88, 1.88]
1.2 at 6 months 1 98 Mean Difference (IV, Fixed, 95% CI) -8.0 [-12.41, -3.59]
2 Bleeding after treatment (days) 1 91 Mean Difference (IV, Fixed, 95% CI) -3.0 [-7.75, 1.75]
4 Patient dissatisfaction with 1 97 Risk Ratio (M-H, Fixed, 95% CI) 0.46 [0.23, 0.91]
treatment
Comparison 9. Antiprogestin vs placebo (LNG subcutaneous implant/Prophylactic)
No. of No. of
treatment

Comparison 10. Antiprogestin vs placebo (Implanon/Therapeutic)
No. of No. of
1 Side effects related to treatment 1 178 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.58, 1.28]
1.1 Any side effects 1 89 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.61, 1.42]
1.2 Nausea/vomiting 1 89 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.23, 1.80]
Comparison 12. Antiprogestin vs placebo (Minipill/Prophylactic)
No. of No. of
1 Percentage of women with B/S 1 260 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.71, 1.27]
episodes starting day 8-28
1.1 Cycle 1 1 100 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.59, 1.18]
2 Discontinuation of the 1 103 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.14, 6.70]
of bleeding
3 Percentage of women having 1 103 Risk Ratio (M-H, Random, 95% CI) 1.08 [0.79, 1.47]
side effects related to
treatment (headache,emotional
lability,acne, breast pain).
4 Discontinuation of the 1 103 Risk Ratio (M-H, Random, 95% CI) 0.74 [0.17, 3.12]
contraceptive because of side
effects.
Comparison 13. Antiprogestin and estrogen vs placebo (Implanon/Therapeutic)
No. of No. of
during treatment (# women)
2 Side effects related to treatment 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 Any side effects 1 90 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.84, 1.75]
2.2 Nausea/Vomiting 2 169 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.18, 1.38]
2.3 Headache 1 79 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.11, 3.68]
3 Number of days to stop Other data No numeric data
bleeding/spotting following
initiation of treatment
method
method at 90 days following
Comparison 14. Venotonic vs placebo (Minipill/Therapeutic)
No. of No. of
Comparison 15. Vitamin E vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
because of side-effects
4 Side-effects related to treatment 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
4.2 Gastrointestinal 1 243 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.20, 1.32]
discomfort
Comparison 16. NSAIDs vs placebo (LNG sub-cutaneous implant/Therapeutic)
No. of No. of
treatment
method
of bleeding
due to side-effects
discomfort
treatment
9 Bleeding/spotting after treatment 1 86 Mean Difference (IV, Fixed, 95% CI) -0.20 [-1.24, 0.84]
(# days)
Comparison 17. Vitamin E + NSAID vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
due to side-effects
discomfort
Comparison 18. NSAID vs placebo (DMPA/Therapeutic)
No. of No. of
during treatment
discomfort

Comparison 19. Selective estrogen receptor modulator vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
during treatment
treatment
method
of bleeding
discomfort
treatment
Comparison 20. Antifibrinolytic vs placebo (LNG subcutaneous implant/Therapeutic)
No. of No. of
during treatment
treatment
Comparison 21. Matrix metalloproteinase inhibitor vs placebo (Implanon/Therapeutic).
No. of No. of
2.1 Any side effect 1 90 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.53, 1.29]
method
Comparison 22. Matrix metalloproteinase inhibitor vs placebo (DMPA/Therapeutic)
No. of No. of
1 Women who stopped bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
within10 days of starting
treatment.
2 Number of bleeding days in the 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
first 3 months after treatment.
2.1 Number of bleeding days 1 65 Mean Difference (IV, Fixed, 95% CI) -0.58 [-2.76, 1.60]
in the first month
2.2 Number of bleeding days 1 58 Mean Difference (IV, Fixed, 95% CI) 0.14 [-2.19, 2.47]
in the second month
2.3 Number of bleeding days 1 58 Mean Difference (IV, Fixed, 95% CI) -0.10 [-2.43, 2.23]
in the third month
3 Number of spotting days in 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
the first three months after
treatment
3.1 Number of spotting days 1 65 Mean Difference (IV, Fixed, 95% CI) 0.95 [-1.78, 3.68]
in the first month
3.2 Number of spotting days 1 58 Mean Difference (IV, Fixed, 95% CI) -0.93 [-3.82, 1.96]
in the second month
3.3 Number of spotting days 1 58 Mean Difference (IV, Fixed, 95% CI) 0.06 [-1.37, 1.49]
in the third month
4 Women with bleeding-free 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
interval equal to or less than15
days in the first 3 months after
start of treatment.
4.1 First month 1 65 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.70, 1.48]
4.2 Second month 1 58 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.60, 1.23]
4.3 Third month 1 58 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.64, 1.28]
5 Women who discontinued 1 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only
DMPA
6 Women who lost to follow up 1 Peto Odds Ratio (Peto, Fixed, 95% CI) Subtotals only

Comparison 23. Antifibrinolytic vs placebo (DMPA/Therapeutic)
No. of No. of
during treatment (# of women)
2 Unacceptable bleeding after 1 99 Mean Difference (IV, Fixed, 95% CI) -11.8 [-13.93, -9.67]
treatment
Comparison 24. NSAID vs Placebo (Implanon/Therapeutic)
No. of No. of
1 Unaccetable bleeding after 1 46 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
treatment
during treatment (# of women)
3.1 Abdominal discomfort 1 46 Risk Ratio (M-H, Fixed, 95% CI) 7.0 [0.38, 128.33]
3.3 Breast tenderness 1 46 Risk Ratio (M-H, Fixed, 95% CI) 0.2 [0.01, 3.95]
Comparison 25. Antiprogestin vs Placebo (LNG-IUS/Prophylactic)
No. of No. of
1 Unacceptable bleeding after 1 Mean Difference (IV, Fixed, 95% CI) Subtotals only
treatment (% days)
1.1 Treatment cycle 1 (28 1 123 Mean Difference (IV, Fixed, 95% CI) -10.60 [-18.68, -2.
days) 52]
1.2 Post treatment cycle 2 (28 1 123 Mean Difference (IV, Fixed, 95% CI) -1.60 [-9.57, 6.37]
days)
1.3 Post treatment cycle 3 (28 1 118 Mean Difference (IV, Fixed, 95% CI) 9.50 [1.48, 17.52]
days)
2 Discontinuation of the 1 136 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.03, 3.03]
3.1 Tendency to gain weight 1 116 Risk Ratio (M-H, Fixed, 95% CI) 6.31 [1.50, 26.53]
treatment (number of women
non-compliant)
5 Blood loss during treatment 1 112 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.85, 1.08]
(perceived improvement)
Comparison 26. Vitamin C vs Placebo (DMPA/Prophylactic)
No. of No. of
1 Bleeding during treatment (# 1 27 Mean Difference (IV, Fixed, 95% CI) 1.0 [-3.16, 5.16]
days)
1.1 First treatment cycle 1 27 Mean Difference (IV, Fixed, 95% CI) 1.0 [-3.16, 5.16]
Comparison 27. Antiprogestin and matrix metalloproteinase inhibitor vs Placebo (Implanon/Therapeutic)
No. of No. of

method
Comparison 28. Estrogen and matrix metalloproteinase inhibitor vs Placebo (Implanon/Therapeutic)
No. of No. of


Treatment of Vaginal Bleeding Irregluarities Induced by Progestin Only Contraceptives

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Treatment of Vaginal Bleeding Irregluarities Induced by Progestin Only Contraceptives

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Treatment of vaginal bleeding irregularities induced by

progestin only contraceptives (Review)

Abdel-Aleem H, d’Arcangues C, Vogelsong KM, Gaffield ML, Gülmezoglu AM

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review)

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) i

Treatment of vaginal bleeding irregularities induced by

Editorial group: Cochrane Fertility Regulation Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Evaluation of treatments for vaginal bleeding induced by progestin-only contraceptives

BACKGROUND injectable contraceptive currently available, norethisterone enan-

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 3

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 4

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 5

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 6

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 7

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 8

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 9

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 10

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 11

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 12

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 13

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 14

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 15

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 16

Several other types of treatments have been shown to be some-

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 17

Implications for research ACKNOWLEDGEMENTS

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 20

Newton 1994 Shaaban 1984

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 21

Characteristics of included studies [ordered by study ID]

Methods Randomized trial

Outcomes Percent of women who stopped bleeding during the treatment:

Bias Authors’ judgement Support for judgement

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 22

Allocation concealment (selection bias) Low risk A - Adequate

Blinding (performance bias and detection Low risk A - Adequate

Drop outs (%) > 10 Low risk A - Adequate

Methods Randomized trial

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk closed sealed envelopes

Blinding (performance bias and detection Low risk Double blinded

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 23

Drop outs (%) > 10 High risk 14.7 %

Methods Randomized trial

Interventions EE: 50 mcg/day x 20 days, orally;

Outcomes Effectiveness of treatment, as measured by a cessation of B/S in 3 days of treatment or

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Blinding (performance bias and detection High risk C - inadequate

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 24

Methods Randomized trial

Outcomes The number of days of bleeding and/or spotting during treatment

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk A - Adequate

Blinding (performance bias and detection Low risk A - Adequate

Drop outs (%) > 10 Low risk A - Adequate

Treatment of vaginal bleeding irregularities induced by progestin only contraceptives (Review) 25

Methods Randomized trial

Participants 64 Norplant users in the first year of use.

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear