-
The Cochrane Database of Systematic... Aug 2016Obesity has reached epidemic proportions around the world. Effectiveness of hormonal contraceptives may be related to metabolic changes in obesity or to greater body... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Obesity has reached epidemic proportions around the world. Effectiveness of hormonal contraceptives may be related to metabolic changes in obesity or to greater body mass or body fat. Hormonal contraceptives include oral contraceptives (OCs), injectables, implants, hormonal intrauterine contraception (IUC), the transdermal patch, and the vaginal ring. Given the prevalence of overweight and obesity, the public health impact of any effect on contraceptive efficacy could be substantial.
OBJECTIVES
To examine the effectiveness of hormonal contraceptives in preventing pregnancy among women who are overweight or obese versus women with a lower body mass index (BMI) or weight.
SEARCH METHODS
Until 4 August 2016, we searched for studies in PubMed (MEDLINE), CENTRAL, POPLINE, Web of Science, ClinicalTrials.gov, and ICTRP. We examined reference lists of pertinent articles to identify other studies. For the initial review, we wrote to investigators to find additional published or unpublished studies.
SELECTION CRITERIA
All study designs were eligible. The study could have examined any type of hormonal contraceptive. Reports had to contain information on the specific contraceptive methods used. The primary outcome was pregnancy. Overweight or obese women must have been identified by an analysis cutoff for weight or BMI (kg/m(2)).
DATA COLLECTION AND ANALYSIS
Two authors independently extracted the data. One entered the data into RevMan and a second verified accuracy. The main comparisons were between overweight or obese women and women of lower weight or BMI. We examined the quality of evidence using the Newcastle-Ottawa Quality Assessment Scale. Where available, we included life-table rates. We also used unadjusted pregnancy rates, relative risk (RR), or rate ratio when those were the only results provided. For dichotomous variables, we computed an odds ratio with 95% confidence interval (CI).
MAIN RESULTS
With 8 studies added in this update, 17 met our inclusion criteria and had a total of 63,813 women. We focus here on 12 studies that provided high, moderate, or low quality evidence. Most did not show a higher pregnancy risk among overweight or obese women. Of five COC studies, two found BMI to be associated with pregnancy but in different directions. With an OC containing norethindrone acetate and ethinyl estradiol (EE), pregnancy risk was higher for overweight women, i.e. with BMI ≥ 25 versus those with BMI < 25 (reported relative risk 2.49, 95% CI 1.01 to 6.13). In contrast, a trial using an OC with levonorgestrel and EE reported a Pearl Index of 0 for obese women (BMI ≥ 30) versus 5.59 for nonobese women (BMI < 30). The same trial tested a transdermal patch containing levonorgestrel and EE. Within the patch group, obese women in the "treatment-compliant" subgroup had a higher reported Pearl Index than nonobese women (4.63 versus 2.15). Of five implant studies, two that examined the six-capsule levonorgestrel implant showed differences in pregnancy by weight. One study showed higher weight was associated with higher pregnancy rate in years 6 and 7 combined (reported P < 0.05). In the other, pregnancy rates differed in year 5 among the lower weight groups only (reported P < 0.01) and did not involve women weighing 70 kg or more.Analysis of data from other contraceptive methods indicated no association of pregnancy with overweight or obesity. These included depot medroxyprogesterone acetate (subcutaneous), levonorgestrel IUC, the two-rod levonorgestrel implant, and the etonogestrel implant.
AUTHORS' CONCLUSIONS
The evidence generally did not indicate an association between higher BMI or weight and effectiveness of hormonal contraceptives. However, we found few studies for most contraceptive methods. Studies using BMI, rather than weight alone, can provide information about whether body composition is related to contraceptive effectiveness. The contraceptive methods examined here are among the most effective when used according to the recommended regimen.We considered the overall quality of evidence to be low for the objectives of this review. More recent reports provided evidence of varying quality, while the quality was generally low for older studies. For many trials the quality would be higher for their original purpose rather than the non-randomized comparisons here. Investigators should consider adjusting for potential confounding related to BMI or contraceptive effectiveness. Newer studies included a greater proportion of overweight or obese women, which helps in examining effectiveness and side effects of hormonal contraceptives within those groups.
Topics: Body Mass Index; Body Weight; Contraception; Contraceptive Agents, Female; Female; Humans; Obesity; Overweight; Pregnancy; Pregnancy Rate; Pregnancy, Unplanned; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 27537097
DOI: 10.1002/14651858.CD008452.pub4 -
Contraception Dec 2016Women with depressive or bipolar disorders are at an increased risk for unintended pregnancy. (Review)
Review
BACKGROUND
Women with depressive or bipolar disorders are at an increased risk for unintended pregnancy.
OBJECTIVE
To examine the safety of hormonal contraception among women with depressive and bipolar disorders.
METHODS
We searched for articles published through January 2016 on the safety of using any hormonal contraceptive method among women with depressive or bipolar disorders, including those who had been diagnosed clinically or scored above threshold levels on a validated screening instrument. Outcomes included changes in symptoms, hospitalization, suicide and modifications in medication regimens such as increase or decrease in dosage or changes in type of drug.
RESULTS
Of 2376 articles, 6 met the inclusion criteria. Of three studies that examined women clinically diagnosed with depressive or bipolar disorder, one found that oral contraceptives (OCs) did not significantly change mood across the menstrual cycle among women with bipolar disorder, whereas mood did significantly change across the menstrual cycle among women not using OCs; one found no significant differences in the frequency of psychiatric hospitalizations among women with bipolar disorder who used depot medroxyprogesterone acetate (DMPA), intrauterine devices (IUDs) or sterilization; and one found no increase in depression scale scores among women with depression using and not using OCs, for both those treated with fluoxetine and those receiving placebo. Of three studies that examined women who met a threshold for depression on a screening instrument, one found that adolescent girls using combined OCs (COCs) had significantly improved depression scores after 3 months compared with placebo, one found that OC users had similar odds of no longer being depressed at follow-up compared with nonusers, and one found that COC users were less frequently classified as depressed over 11 months than IUD users.
CONCLUSIONS
Limited evidence from six studies found that OC, levonorgestrel-releasing IUD and DMPA use among women with depressive or bipolar disorders was not associated with worse clinical course of disease compared with no hormonal method use.
Topics: Bipolar Disorder; Contraceptives, Oral; Depressive Disorder; Equipment Safety; Female; Humans; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate; Pregnancy; Pregnancy, Unplanned; Psychiatric Status Rating Scales; Risk Assessment
PubMed: 27364100
DOI: 10.1016/j.contraception.2016.06.012 -
Contraception Dec 2016Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about... (Review)
Review
BACKGROUND
Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about progestin-only contraceptives (POCs) and thrombosis risk.
OBJECTIVES
The objective was to identify evidence regarding the risk of venous thromboembolism (VTE) or arterial thromboembolism [stroke or acute myocardial infarction (AMI)] among women using POCs.
METHODS
We searched the PubMed database for all articles published from database inception through January 2016 for studies examining thrombosis among women using POCs. We included studies which examined women with medical conditions associated with thrombosis risk, as well as studies of women in the general population (either without these conditions or who were not specified to have these conditions). Hormonal contraceptives of interest included progestin-only pills (POPs), injectables, implants and levonorgestrel-releasing intrauterine devices (LNG-IUDs). Outcomes of interest included VTE, stroke and AMI.
RESULTS
There were 26 articles of good to poor quality that met inclusion criteria; 9 studies examined women with medical conditions and 20 examined women in the general population. Two studies found that, among smokers and women with certain thrombogenic mutations, use of depot medroxyprogesterone acetate (DMPA) had elevated odds of VTE compared with nonsmokers or those without mutations, although confidence intervals were wide and overlapped with odds among nonusers. One study found that, among women with previous VTE, use of POCs (including DMPA) was associated with a nonsignificant increased odds of recurrent VTE (all of which were among DMPA users); two other studies that examined POCs other than DMPA did not observe an association with recurrent VTE. Two studies found that use of DMPA among healthy women was also associated with increased odds of VTE. Two studies found that use of POCs for therapeutic indications was associated with increased odds of VTE. Studies did not find increased odds of VTE with POPs for contraceptive purposes, implants or LNG-IUDs nor were there increased odds of stroke or AMI with any POCs.
CONCLUSION
The majority of evidence identified by this systematic review did not suggest an increase in odds for venous or arterial events with use of most POCs. Limited evidence suggested increased odds of VTE with use of injectables (three studies) and use of POCs for therapeutic indications (two studies, one with POCs unspecified and the other with POPs). Any increase in risk likely translates to a small increase in absolute numbers of thrombotic events at the population level.
Topics: Contraception; Female; Humans; Myocardial Infarction; Progestins; Risk Assessment; Stroke; Venous Thromboembolism; Weight Gain
PubMed: 27153743
DOI: 10.1016/j.contraception.2016.04.014 -
Contraception Sep 2016Depot medroxyprogesterone acetate (DMPA), a progestogen-only contraceptive injectable, has traditionally been formulated as a crystalline suspension delivered... (Review)
Review
CONTEXT
Depot medroxyprogesterone acetate (DMPA), a progestogen-only contraceptive injectable, has traditionally been formulated as a crystalline suspension delivered intramuscularly (IM) at a dose of 150mg/1.0mL. A new, lower dose formulation of DMPA (104mg/0.65mL) has been developed for subcutaneous administration (SC). Given its increasing global availability and public health relevance, DMPA-SC was prioritized for inclusion as a new method referenced in the World Health Organization (WHO) Medical Eligibility Criteria for Contraceptive Use (MEC), 5th Edition.
OBJECTIVE
This systematic review evaluated the published peer-reviewed literature regarding the safety of DMPA-SC among women with various characteristics or medical conditions. Results of this review informed the decision-making of a WHO Guideline Development Group in order to include recommendations on contraceptive eligibility within the revised MEC.
METHODS
We searched PubMed and Cochrane Library databases to identify all relevant evidence published in peer-reviewed journals regarding the safety of DMPA-SC when used by women of reproductive age, particularly those with select characteristics or conditions specified in the MEC, from inception through June 2015. The quality of each individual study was assessed using the system for grading evidence developed by the United States Preventive Services Task Force.
RESULTS
Fourteen studies met criteria for inclusion. Ten reported results relevant to DMPA users of varying age or with obesity, endometriosis or HIV; four compared the safety of DMPA-SC and DMPA-IM when used by general populations of healthy women. A randomized trial evaluating changes in bone mineral density among adult DMPA-SC and DMPA-IM users demonstrated no differences at 2years of follow-up. Limited evidence reported no consistent differences in weight change or bleeding patterns according to age; however, adolescents (<18years) were not included in any studies. Similar contraceptive efficacy, weight change, bleeding patterns and occurrence of other adverse effects among obese and nonobese DMPA-SC users were observed. Women with endometriosis using DMPA-SC over 6months had minimal decreases in bone mineral density, weight gain, few serious adverse events and experienced improved pain symptoms. Women living with HIV tolerated injection of DMPA-SC with rare complications. DMPA-SC and DMPA-IM also show therapeutic equivalence and similar effects on weight gain, changes in bleeding patterns and reports of other adverse effects when these different delivery systems were used by general populations of women.
CONCLUSION
Evidence for use of DMPA-SC by women with select conditions and characteristics including age, obesity, endometriosis or HIV demonstrates that this method can generally be used safely in these contexts. Further, DMPA-SC and DMPA-IM appear to be therapeutically equivalent with similar safety profiles when used by healthy women.
Topics: Bone Density; Contraceptive Agents, Female; Delayed-Action Preparations; Endometriosis; Female; HIV Infections; Humans; Injections, Intramuscular; Injections, Subcutaneous; Medroxyprogesterone Acetate; Obesity; Pain; Patient Satisfaction; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Weight Gain; World Health Organization
PubMed: 26874275
DOI: 10.1016/j.contraception.2016.02.003 -
Breast Cancer Research and Treatment Jan 2016This systematic review summarizes research on the use of progestin and breast cancer risk. Although mainly used for contraception, progestin can help treat menstrual... (Meta-Analysis)
Meta-Analysis Review
This systematic review summarizes research on the use of progestin and breast cancer risk. Although mainly used for contraception, progestin can help treat menstrual disorders, and benign breast, uterine, and ovarian diseases. Breast cancer is the leading site of new, non-skin, cancers in females in the United States, and possible factors that may modulate breast cancer risk need to be identified. ProQuest (Ann Arbor, MI) and PubMed-Medline (US National Library of Medicine, Bethesda MD, USA) databases were used to search for epidemiologic studies from 2000 to 2015 that examined the association between progestin and breast cancer. Search terms included epidemiologic studies + progesterone or progestin or progestogen or contraceptive or contraceptive agents + breast cancer or breast neoplasms. A total of six studies were included in the review. Five of the six studies reported no association between progestin-only formulations (including norethindrone oral contraceptives, depot medroxyprogesterone acetate, injectable, levonorgestrel system users, implantable and intrauterine devices) and breast cancer risk. Duration of use was examined in a few studies with heterogeneous results. Unlike studies of other oral contraceptives, studies indicate that progestin-only formulations do not increase the risk of breast cancer, although the literature is hampered by small sample sizes. Future research is needed to corroborate these findings, as further understanding of synthetic progesterone may initiate new prescription practices or guidelines for women's health.
Topics: Breast Neoplasms; Contraceptive Agents, Female; Female; Humans; Levonorgestrel; Odds Ratio; Progestins; Risk
PubMed: 26700034
DOI: 10.1007/s10549-015-3663-1 -
Contraception Sep 2016Postpartum women need effective contraception. Concerns have been raised that use of progestogen-only contraceptives (POCs) may affect breastfeeding performance and... (Review)
Review
BACKGROUND
Postpartum women need effective contraception. Concerns have been raised that use of progestogen-only contraceptives (POCs) may affect breastfeeding performance and infant health outcomes.
OBJECTIVES
We investigated the clinical outcomes of breastfeeding duration, initiation of supplemental feeding and weaning, as well as infant outcomes including infant growth, health and development among breastfeeding women using POCs compared with breastfeeding women not using POCs.
SEARCH STRATEGY
We searched the PubMed database for all articles published from database inception through December 2014.
SELECTION CRITERIA
We included primary research studies of breastfeeding women of any age or parity who received POCs, including progestogen-only pills, injectables, implants or hormonal intrauterine devices (IUDs). The main outcomes were breastfeeding performance (as measured by initiation, continuation, frequency and exclusivity of breastfeeding) and infant health (as measured by growth, development or adverse health effects).
RESULTS
Forty-nine articles reporting on 47 different studies were identified that investigated the use of POCs in breastfeeding women and reported clinically relevant outcomes of infant growth, health or breastfeeding performance. Studies ranged from poor to fair methodological quality and generally failed to show negative effects of the use of POCs on breastfeeding outcomes or on infant growth or development. One randomized controlled trial (RCT) raises concerns that immediate insertion of the levonorgestrel IUD postpartum may be associated with poorer breastfeeding performance when compared with delayed insertion, although two other RCTs evaluating early etonogestrel implants compared with delayed initiation of implants or depot medroxyprogesterone acetate failed to find such an association.
CONCLUSION
The preponderance of evidence fails to demonstrate adverse breastfeeding outcomes or negative health outcomes in infants such as restricted growth, health problems or impaired development. Evidence newly added to this review was largely consistent with previous evidence.
Topics: Breast Feeding; Child Development; Contraception; Contraceptives, Oral, Hormonal; Drug Implants; Female; Humans; Infant; Intrauterine Devices; Levonorgestrel; Medroxyprogesterone Acetate; Progestins; Randomized Controlled Trials as Topic
PubMed: 26410174
DOI: 10.1016/j.contraception.2015.09.010 -
Contraception Dec 2015Use of contraception lowers a woman's risk of experiencing an ectopic pregnancy. In the case of method failure, however, progestin-only contraceptives may be more likely... (Review)
Review
BACKGROUND
Use of contraception lowers a woman's risk of experiencing an ectopic pregnancy. In the case of method failure, however, progestin-only contraceptives may be more likely to result in ectopic pregnancies than some other methods such as combined hormonal and barrier contraceptives.
OBJECTIVE
To describe ectopic pregnancy risk associated with use of implants and progestin-only injectable contraceptives through a systematic review of published studies.
DATA SOURCES
We searched electronic databases for articles in any language published through May 2015 describing studies of progestin-only injectables and implants. We also searched bibliographies and review articles for additional studies.
STUDY SELECTION AND EXTRACTION
Studies that reported any pregnancies were included in the review. Independent data extraction was performed by two authors based on predefined data fields, and where possible, we calculated the proportion of pregnancies that were ectopic and the ectopic pregnancy incidence rate per 1000 woman-years.
RESULTS
Fifty-three studies of implants and 28 studies of injectables were identified; 79% reported pregnancy location. The proportion of ectopic pregnancy ranged from 0 to 100% with an incidence of 0-2.9 per 1000 woman-years in studies of marketed levonorgestrel implants. Studies of etonogestrel implants and the injectables, depot-medroxyprogesterone acetate and norethisterone enanthate, reported few ectopic pregnancies.
CONCLUSION
Progestin-only contraceptive implants and injectables protect against ectopic pregnancy by being highly effective in preventing pregnancy overall; however, the absolute risk of ectopic pregnancy varies by type of progestin. Risk of ectopic pregnancy should not be a deterrent for use or provision of these methods.
Topics: Contraception; Contraceptive Agents, Female; Desogestrel; Drug Implants; Female; Humans; Incidence; Injections; Levonorgestrel; Medroxyprogesterone Acetate; Norethindrone; Pregnancy; Pregnancy, Ectopic; Progestins
PubMed: 26363431
DOI: 10.1016/j.contraception.2015.08.016 -
The Cochrane Database of Systematic... Jul 2015Age-related decline in bone mass increases the risk of skeletal fractures, especially those of the hip, spine, and wrist. Steroidal contraceptives have been associated... (Review)
Review
BACKGROUND
Age-related decline in bone mass increases the risk of skeletal fractures, especially those of the hip, spine, and wrist. Steroidal contraceptives have been associated with changes in bone mineral density in women. Whether such changes affect the risk of fractures later in life is unclear. Hormonal contraceptives are among the most effective and most widely-used contraceptives. Concern about fractures may limit the use of these effective contraceptives. Observational studies can collect data on premenopausal contraceptive use as well as fracture incidence later in life.
OBJECTIVES
We systematically reviewed the evidence from observational studies of hormonal contraceptive use for contraception and the risk of fracture in women.
SEARCH METHODS
Through June 2015, we searched for observational studies. The databases included PubMed, POPLINE, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, EMBASE, CINAHL, and Web of Science. We also searched for recent clinical trials through ClinicalTrials.gov and the ICTRP. For other studies, we examined reference lists of relevant articles and wrote to investigators for additional reports.
SELECTION CRITERIA
We included cohort and case-control studies of hormonal contraceptive use. Interventions included comparisons of a hormonal contraceptive with a non-hormonal contraceptive, no contraceptive, or another hormonal contraceptive. The primary outcome was the risk of fracture.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted the data. One author entered the data into RevMan, and a second author verified accuracy. We examined the quality of evidence using the Newcastle-Ottawa Quality Assessment Scale (NOS), developed for case-control and cohort studies. Sensitivity analysis included studies of moderate or high quality based on our assessment with the NOS.Given the need to control for confounding factors in observational studies, we used adjusted estimates from the models as reported by the authors. Where we did not have adjusted analyses, we calculated the odds ratio (OR) with 95% confidence interval (CI). Due to varied study designs, we did not conduct meta-analysis.
MAIN RESULTS
We included 14 studies (7 case-control and 7 cohort studies). These examined oral contraceptives (OCs), depot medroxyprogesterone acetate (DMPA), and the hormonal intrauterine device (IUD). This section focuses on the sensitivity analysis with six studies that provided moderate or high quality evidence.All six studies examined oral contraceptive use. We noted few associations with fracture risk. One cohort study reported OC ever-users had increased risk for all fractures (RR 1.20, 95% CI 1.08 to 1.34). However, a case-control study with later data from a subset reported no association except for those with 10 years or more since use (OR 1.55, 95% CI 1.03 to 2.33). Another case-control study reported increased risk only for those who had 10 or more prescriptions (OR 1.09, 95% CI 1.03 to 1.16). A cohort study of postmenopausal women found no increased fracture risk for OC use after excluding women with prior fracture. Two other studies found little evidence of association between OC use and fracture risk. A cohort study noted increased risk for subgroups, such as those with longer use or specific intervals since use. A case-control study reported increased risk for any fracture only among young women with less than average use.Two case-control studies also examined progestin-only contraceptives. One reported increased fracture risk for DMPA ever-use (OR 1.44, 95% CI 1.01 to 2.06), more than four years of use (OR 2.16, 95% CI 1.32 to 3.53), and women over 50 years old. The other reported increased risk for any past use, including one or two prescriptions (OR 1.17, 95% CI 1.07 to 1.29) and for current use of 3 to 9 prescriptions (OR 1.36, 95% CI 1.15 to 1.60) or 10 or more (OR 1.54, 95% CI 1.33 to 1.78). For the levonorgestrel-releasing IUD, one study reported reduced fracture risk for ever-use (OR 0.75, 95% CI 0.64 to 0.87) and for longer use.
AUTHORS' CONCLUSIONS
Observational studies do not indicate an overall association between oral contraceptive use and fracture risk. Some reported increased risk for specific user subgroups. DMPA users may have an increased fracture risk. One study indicated hormonal IUD use may be associated with decreased risk. Observational studies need adjusted analysis because the comparison groups usually differ. Investigators should be clear about the variables examined in multivariate analysis.
Topics: Age Factors; Case-Control Studies; Cohort Studies; Contraceptives, Oral, Hormonal; Female; Fractures, Bone; Humans; Intrauterine Devices, Medicated; Medroxyprogesterone Acetate; Observational Studies as Topic; Progestins; Time Factors
PubMed: 26195091
DOI: 10.1002/14651858.CD009849.pub3 -
American Journal of Preventive Medicine Aug 2015This systematic review evaluated the evidence on the impact of family planning reminder systems-interventions intended to remind patients of behaviors to achieve... (Review)
Review
CONTEXT
This systematic review evaluated the evidence on the impact of family planning reminder systems-interventions intended to remind patients of behaviors to achieve reproductive health goals (e.g., daily text messages reminding oral contraceptive [OC] users to take a pill)-to provide information to guide national recommendations on quality family planning services.
EVIDENCE ACQUISITION
Multiple databases including PubMed were searched during 2010-2011 for peer-reviewed articles published in English from January 1985 through February 2011 describing studies evaluating reminder systems to improve family planning outcomes. Studies were excluded if they focused primarily on HIV or sexually transmitted infection prevention, focused solely on men, or were conducted outside the U.S., Europe, Australia, or New Zealand.
EVIDENCE SYNTHESIS
The initial search identified 16,129 articles, five of which met the inclusion criteria. Three studies examined the impact of OC reminder systems; two found a statistically significant positive impact on correct use. Two studies examined the impact of reminder systems among depot medroxyprogesterone acetate (DMPA) users; one found a statistically significant positive impact on correct use.
CONCLUSIONS
Although mixed support was found for the effectiveness of reminder system interventions on correct use of OCs and DMPA, the highest-quality evidence yielded null findings. The evidence base would be strengthened by the development of additional studies, especially RCTs, which objectively measure outcomes, examine additional contraceptive methods, and have sufficient sample sizes to detect behavioral outcomes at least 12 months post-intervention.
Topics: Australia; Contraception; Europe; Family Planning Services; Female; Humans; Male; New Zealand; Pregnancy; Pregnancy, Unplanned; Reminder Systems; Text Messaging; United States
PubMed: 26190847
DOI: 10.1016/j.amepre.2015.03.018 -
The Cochrane Database of Systematic... Mar 2015Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects.
OBJECTIVES
To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms.
SEARCH METHODS
We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014.
SELECTION CRITERIA
Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria.
MAIN RESULTS
Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) -0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm(3), 95% CI 77.58 to 606.80, 2 studies, 32 women, I(2) = 0%, low quality evidence).Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I(2) = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm(3), 95% CI= 8.13 to 39.66, 6 studies, 365 women, I(2) = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm(3), 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm(3), 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow-up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings.
AUTHORS' CONCLUSIONS
There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.
Topics: Antineoplastic Agents, Hormonal; Bone Density; Bone Density Conservation Agents; Drug Therapy, Combination; Estriol; Female; Gonadotropin-Releasing Hormone; Humans; Isoflavones; Leiomyoma; Medroxyprogesterone; Norpregnenes; Quality of Life; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Uterine Hemorrhage; Uterine Neoplasms
PubMed: 25793972
DOI: 10.1002/14651858.CD010854.pub2