1 EML 2015 – application for the levonorgestrel‐releasing intrauterine system (LNG‐IUS) General items 1. Summary statement of the proposal for inclusion, change or deletion The levonorgestrel‐releasing intrauterine system (LNG‐IUS) is a T‐shaped IUD polyethylene device that is 32 mm long and 32 mm wide with a steroid reservoir containing 52 mg of levonorgestrel that is released at an initial rate of 20 μg daily. This hormone acts like the natural hormone progesterone and is widely used in other contraceptive methods, such as implants and oral contraceptive pills. It is highly effective, with a typical‐use first year pregnancy rate of 0.1% – similar to surgical tubal occlusion. It is approved for 5 years of contraceptive use, and there is evidence that it can be effective for up to 7 years of continuous use. After removal, there is rapid return to fertility, with 1‐year life‐table pregnancy rates of 89 per 100 for women less than 30 years of age. Most users experience a dramatic reduction in menstrual bleeding, and about 15% to 20% of women become amenorrheic 1 year after insertion. The Levonorgestrel Intrauterine System (LNG IUS) was developed by Population Council and Bayer Schering Pharma Oy and is currently distributed by Bayer Schering Pharma in the private market. The LNG IUS is now also available to the public‐sector audience, through various mediums of distribution (amongst others the ICA Foundation). The clinical indication for the LNG IUS is contraception during the reproductive age and 4 weeks postpartum. The target population for this method is women of reproductive age, from 4 weeks up to one year postpartum who are actively breastfeeding at least 4 times per day. The method is WHO Medical Eligibility Criteria (since the third edition in 2004), and the Selected Practice Recommendations for Contraceptive Use (sine the second edition in 2004). There is currently no medicated intra‐uterine device available on the EML. Apart from this the other established indications are the treatment of heavy menstrual bleeding as well as endometrial protection during estrogen therapy for menopausal symptoms 2. Name of the focal point in WHO submitting or supporting the application (where relevant) Department of Reproductive Health and Research (RHR) Dr Petrus STEYN 3. Name of the organization(s) consulted and/or supporting the application N/A 4. International Nonproprietary Name (INN, generic name) of the medicine Levonorgestrel‐releasing Intrauterine System, LNG‐20 IUS 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Dosage: 52 mg of levonorgestrel is contained in the reservoir of the intrauterine system (IUS). 6. International availability ‐ sources, of possible manufacturers and trade names
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EML 2015 – application for the levonorgestrel‐releasing intrauterine system (LNG‐IUS)
General items 1. Summary statement of the proposal for inclusion, change or deletion The levonorgestrel‐releasing intrauterine system (LNG‐IUS) is a T‐shaped IUD polyethylene device that is 32 mm long and 32 mm wide with a steroid reservoir containing 52 mg of levonorgestrel that is released at an initial rate of 20 μg daily. This hormone acts like the natural hormone progesterone and is widely used in other contraceptive methods, such as implants and oral contraceptive pills. It is highly effective, with a typical‐use first year pregnancy rate of 0.1% – similar to surgical tubal occlusion. It is approved for 5 years of contraceptive use, and there is evidence that it can be effective for up to 7 years of continuous use. After removal, there is rapid return to fertility, with 1‐year life‐table pregnancy rates of 89 per 100 for women less than 30 years of age. Most users experience a dramatic reduction in menstrual bleeding, and about 15% to 20% of women become amenorrheic 1 year after insertion. The Levonorgestrel Intrauterine System (LNG IUS) was developed by Population Council and Bayer Schering Pharma Oy and is currently distributed by Bayer Schering Pharma in the private market. The LNG IUS is now also available to the public‐sector audience, through various mediums of distribution (amongst others the ICA Foundation). The clinical indication for the LNG IUS is contraception during the reproductive age and 4 weeks postpartum. The target population for this method is women of reproductive age, from 4 weeks up to one year postpartum who are actively breastfeeding at least 4 times per day. The method is WHO Medical Eligibility Criteria (since the third edition in 2004), and the Selected Practice Recommendations for Contraceptive Use (sine the second edition in 2004). There is currently no medicated intra‐uterine device available on the EML. Apart from this the other established indications are the treatment of heavy menstrual bleeding as well as endometrial protection during estrogen therapy for menopausal symptoms
2. Name of the focal point in WHO submitting or supporting the application (where relevant)
Department of Reproductive Health and Research (RHR) Dr Petrus STEYN
3. Name of the organization(s) consulted and/or supporting the application N/A
4. International Nonproprietary Name (INN, generic name) of the medicine Levonorgestrel‐releasing Intrauterine System, LNG‐20 IUS 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Dosage: 52 mg of levonorgestrel is contained in the reservoir of the intrauterine system (IUS).
6. International availability ‐ sources, of possible manufacturers and trade names
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The Mirena® IUS is registered in more than 120 countries worldwide, distributed commercially by Bayer Pharma. The LNG IUS provided by the ICA Foundation is registered in three countries (Ghana, Kenya, and Nigeria), but is available through public‐sector. The LNG IUS uses a different inserter than is used for Mirena® and often requires a different registration. [International Contraceptive Access (ICA) Foundation website. www.ica‐foundation.org] Since its introduction into the market, more than 18 million women have selected Mirena® as their method of choice. [Bayer AG 2010 annual report. http://www.annualreport2010.bayer.com/en/bayer‐annual‐report‐2010.pdfx.]
7. Whether listing is requested as an individual medicine or as an example of a therapeutic group Listed as an individual medicine.
8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) Unmet need for contraception remains high in many settings. It is highest among the most vulnerable in society including adolescents, the poor, those living in rural areas and urban slums, people living with HIV, and internally displaced people. In 2012, an estimated 222 million women had an unmet need for contraception [Singh S, Darroch JE. Adding it up: Costs and benefits of contraceptive services. Guttmacher Institute and UNFPA. 2012United Nations Department of Economic and Social Affairs PD. World Contraceptive Patterns 2013 (ST/ESA/SER.A/326). 2013.]; that is, they were at risk of becoming pregnant when they did not wish to conceive, yet were not using a modern method to prevent pregnancy [Jain AK, Obare F, RamaRao S, Askew I. Reducing unmet need by supporting women with met need. International perspectives on sexual and reproductive health. 2013;39(3):133‐41.L. F, E. H. Participation and human rights: impact on women’s and children’s health. What does the literature tell us? Women’s and children’s health: evidence of impact of human rights Geneva, Switzerland: World Health Organization; 2013.] Additionally, many women using contraceptives are not satisfied with their method, potentially putting them at risk for discontinuation without replacement with a more acceptable method, leading to unintended pregnancy. [United Nations Development Programme (UNDP). Investing in development. A practical plan to achieve the Millennium Development Goals. . New York, NY: United Nations Development Programme (UNDP); 2005. Long acting reversible contraception (LARC) has great potential in reducing these pregnancies as they are highly effective and do not rely a great deal on compliance and correct use. They have better continuation rates than short term hormonal contraception and as per definition require administration less than once per cycle or month. [Long‐acting reversible contraception the effective and appropriate use of long‐acting reversible contraception National Collaborating Centre for Women’s and Children’s Health; Update 2013; http://www.nice.org.uk/guidance/cg030].
9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills) Levonorgestrel‐releasing Intrauterine System, LNG‐20 IUS. A steady and local release of 20 μg levonorgestrel per day occurs during the first year, 11 μg per day after 5 years with an average of 14 μg per day over 5 years. Duration: LNG‐releasing IUS is effective for five years. Diagnostic: LNG‐releasing IUS used for reversible contraception. Treatment facilities: The IUS should be inserted during the first seven days of the cycle. Post‐partum insertion can be done six weeks after normal delivery and twelve weeks after caesarean section. The Levonorgestrel‐releasing Intrauterine System, LNG‐20 IUS is included in the WHO medical eligibility criteria for contraceptive use, Fourth edition, 2009, the Selected practice recommendations for contraceptive use, second edition 2004 and the Family Planning Global Handbook for Providers, 2011 update. It will also be included in the
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It is proposed that this medicine should be listed in the core list of the EML.
Public health need and evidence appraisal and synthesis 10. Summary of comparative effectiveness in a variety of clinical settings: The most recent review on the efficacy of contraceptive methods was published and done in 2010 in the European Journal of Reproductive Health Care. The Objectives of the study were to provide a comprehensive and objective summary of contraceptive failure rates for a variety of methods based on a systematic review of the literature. The methodology was to search Medline and Embase using the Ovid interface from January 1990 to February 2008, as well as the reference lists of published articles, to identify studies reporting contraceptive efficacy as a Pearl Index or life‐table estimate. Reports that recruited less than 400 subjects per study group and those covering less than six cycles/six months were excluded. In addition, unlicensed products or those not internationally available, emergency contraception, and vasectomy studies were excluded. Summary of the results: Information was identified and extracted from 139 studies. One‐year Pearl Indices reported for short‐acting user‐dependent hormonal methods were generally less than 2.5. Gross life‐table rates for long‐acting hormonal methods (implants and the levonorgestrel releasing‐intrauterine system [LNG‐IUS]) generally ranged between 0–0.6 per 100 at one year, but wider ranges (0.1–1.5 per 100) were observed for the copper intrauterine devices (0.1–1.4 per 100 for Cu‐IUDs with surface area 300 mm2 and 0.6–1.5 per 100 for those with surface area5300 mm2). The review broadly confirms the hierarchy of contraceptive effectiveness in descending order as: (1) female sterilisation, long‐acting hormonal contraceptives (LNG‐IUS and implants); (2) Cu‐IUDs with300 mm2 surface area; (3) Cu‐IUDs with ˃300 mm2 surface area and short‐acting hormonal contraceptives (injectables, oral contraceptives, the patch and vaginal ring), and (4) barrier methods and natural methods). The article is attached with the summary data on page 7 of the article. [Diana Mansour, Pirjo Inki and Kristina Gemzell‐Danielsson. Efficacy of contraceptive methods: A review of the literature The European Journal of Contraception and Reproductive Health Care, February 2010;15:4–16]
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11. Summary of comparative evidence on safety: In 2010 it was reported that since its introduction into the market, more than 18 million women have selected Mirena® as their method of choice. [Bayer AG 2010 annual report. http://www.annualreport2010.bayer.com/en/bayer‐annual‐report‐2010.pdfx.] A recent overview the developments in the safety and efficacy of the levonorgestrel‐releasing intrauterine system (LNG‐IUS) on established indications, namely contraception, treatment of heavy menstrual bleeding as well as endometrial protection during estrogen therapy for menopausal symptoms were done and published in Expert Rev of Obstet Gynecol. 2013;8(3):235‐247. [Kristina Gemzell‐Danielsson, Pirjo Inki, Oskari Heikinheimo. Safety and Efficacy of the Levonorgestrel‐releasing Intrauterine System. Expert Rev of Obstet Gynecol. 2013;8(3):235‐247.] The review provides an overview of the published literature on the LNG‐IUS from the previous 5 years, focusing on cost–effectiveness, safety‐related outcomes, the use of LNG‐IUS by young and/or nulliparous women as well as by various different patient groups. A PubMed search (up to 27 August 2012) was performed with the following search terms: levonorgestrel‐releasing or Mirena® (Bayer, Leverkusen, Germany) or intrauterine system with the following limits 'English language only and published within the last 5 years'. This resulted in 629 articles, which were manually searched by the authors; the most relevant articles were included by joint decision. Studies not relating to humans were excluded. Furthermore, case reports or small case series were not included in the review as they were not considered to represent robust evidence. Several studies, which addressed various safety‐related outcomes among LNG‐IUS users, were published within the last 5 years and these are summarized in Table 1 at the end of the proposal.
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Through the Continuous Improvement of Research Evidence (CIRE) that informs the development
and update of the WHO Medical Eligibility Criteria an update for Levonorgestrel‐releasing IUD use
among women with heavy or prolonged bleeding is available and done for 2008. Since then and with
the review for the 2015 Edition, no changes to this topic was reported. [Appendix 2]
The objective of the systematic review was to determine from the literature whether it is safe for
women with heavy or prolonged bleeding to use levonorgestrel intrauterine devices (L‐IUD) and to
update the evidence prepared for the 2003 MEC Expert Working Group meeting. MEDLINE and
EMBASE databases were searched for articles (in all languages) published in peer reviewed journals
from January 1966 through March 2006 for articles relevant to heavy or prolonged bleeding and L‐
IUDs. Standard abstract forms and grading systems to summarize and assess the quality of the
evidence.
The search resulted in 219 articles, from which we identified 20 studies as well as 2 systematic
reviews that met our systematic review criteria. “Good” quality evidence from these articles
suggested that women with menorrhagia who use L‐IUDs commonly experience substantial
decreases in menstrual blood loss and pain associated with bleeding, as well as an improved quality
of life. They also experienced common progestogen associated side effects (e.g., bloating, weight,
breast tenderness). Overall, studies reported few serious adverse events. The conclusion were that:
Body of Evidence Grading: I, Good and that “Good" quality evidence suggests that it is safe and
potentially beneficial for woman with heavy or prolonged bleeding to use L‐IUDs.
12. Summary of available data on comparative cost and cost‐effectiveness within the pharmacological class or therapeutic group: Following the above (point 11) for the use of the LNG‐IUS for women with menorrhagia and the following studies reporting the cost‐effectiveness, some in high‐income settings, the benefits will be more evident in low‐resource countries where therapies and surgery are restricted. A study by Blumenthal shows that the levonorgestrel‐releasing intrauterine system (LNG‐IUS) is a cost‐effective treatment of heavy menstrual bleeding in many different countries, and in some settings it is superior to surgical alternatives. Quality of life was shown to be improved to the same degree as following endometrial ablation or hysterectomy. [Blumenthal PD, Dawson L, Hurskainen R. Cost–effectiveness and quality of life associated with heavy menstrual bleeding among women using the levonorgestrel‐releasing intrauterine system. Int. J. Gynaecol. Obstet. 112(3), 171–178 (2011)] In another recent study to evaluate the cost‐effectiveness of the levonorgestrel‐releasing intrauterine system (LNG‐IUS) (in the United States) compared with other therapies for idiopathic heavy menstrual bleeding the LNG‐IUS resulted in the lowest treatment costs and the fewest number of hysterectomies performed over 5 years compared with all other initial strategies and resulted in the most quality‐adjusted life‐years gained among nonsurgical options. Initial treatment with LNG‐IUS is the least costly and most effective option for women desiring to preserve their fertility. [Michael L. Ganz, Dhvani Shah, Risha Gidwani, Anna Filonenko, DrPH3, Wenqing, Jennifer
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Pocoski and Amy Law. The Cost‐Effectiveness of the Levonorgestrel‐Releasing Intrauterine System for the Treatment of Idiopathic Heavy Menstrual Bleeding in the United States. Value in Health Volume 16, Issue 2, March–April 2013, Pages 325–333] LNG‐IUS resulted in the lowest treatment costs and the fewest number of hysterectomies performed over 5 years compared with all other initial strategies and resulted in the most quality‐adjusted life‐years gained among nonsurgical options. Initial treatment with LNG‐IUS is the least costly and most effective option for women desiring to preserve their fertility.
Regulatory information 13. Summary of regulatory status of the medicine (in various countries) The Mirena® IUS is registered in more than 120 countries worldwide, distributed commercially by Bayer Pharma. The LNG IUS provided by the ICA registered in three countries (Ghana, Kenya, and Nigeria), but is available through public‐sector. The LNG IUS uses a different inserter than is used for Mirena® and often requires a different registration. [International Contraceptive Access (ICA) Foundation website. www.ica‐foundation.org] The Mirena is also registered on the following::
US Food and Drug Administration (FDA)
Australian Government, Department of Health and Ageing, Therapeutic Goods 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia) Please verify and list whether the proposed medicine is listed in at least one of the above mentioned Pharmacopeia. N/A 15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary
Levonorgestrel releasing intra-uterine system (Mirena®) • Indications: contraception, hypermenorrhea, endometrial protection during estrogen substitution
• Contraindications: ongoing pregnancy; less than four weeks post‐partum; immediate post‐abortion;
cancer of the cervix and uterus; post septic abortion; breast cancer; anatomical abnormalities
distorting the uterine cavity; pelvic inflammatory disease – current or within the last 3 months;
and liver tumor; severe cirrhosis; thromboembolic diseases; coagulation troubles or use of
anticoagulant medicines; severe anemia; immunosuppressive therapy; frequent sexual partner
changes; hypersensitivity to levonorgestrel or to another component.
• Precautions: exclude endometrial pathology; without any uterine bleeding after six weeks of use, a
pregnancy test is required; epilepsy; diabetes; ovarian cyst; uterine scars; history of ectopic
pregnancy; non steroidal anti‐inflammatory drug use;
Gynecological examination before insertion, 12 weeks after and then annually.
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• Administration: Contraception: LNG‐releasing IUS should be inserted at the end of menstrual
bleeding and before the calculated time of implantation; endometrial protection during estrogen
substitution: insertion can be done at any time when amenorrhea or during the last bleeding days.
For further information, please refer to: Essential Medicines List Secretariat, Medicines Policy, Access and Use Team (PAU), Department of Essential Medicines and Health Products(EMP) World Health Organization 20 Avenue Appia CH‐1211 Geneva 27 Switzerland email: [email protected]
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Table 1. Recent articles describing safety-related outcomes in levonorgestrel-releasing intrauterine system users.
[Kristina Gemzell‐Danielsson, Pirjo Inki, Oskari Heikinheimo. Safety and Efficacy of the Levonorgestrel‐releasing Intrauterine System. Expert Rev of Obstet Gynecol. 2013;8(3):235‐247.]
Study (year) Topic Methodology Main findings
Brahmi et al. (2012)
Pregnancy with IUCD in situ
Review of nine publications reporting on pregnancy outcomes with IUCD in situ
Women with retained IUDs were at the greatest risk of adverse pregnancy outcomes, including spontaneous abortion, preterm delivery, septic abortion and chorioamnionitis. IUCD removal decreased risks but not to the baseline risk of pregnancies without an IUCD
Bahamondes et al. (2006)
BMD Cross-sectional study on LNG-IUS, comparison with matched cohort of copper IUD users
Forearm BMD in LNG-IUS users similar in copper IUD users
Bahamondes et al. (2010)
Prospective study on long-term LNG-IUS vs copper IUD users
Forearm BMD in LNG-IUS users similar as in copper IUD users
Ferreira et al. (2010)
Cardiovascular risk markers
RCT on blood pressure and lipid metabolism in LNG-IUS vs GnRH analog users in endometriosis
Both treatments had no effect on blood pressure. LNG-IUS users had lower total cholesterol and triglyceride values
Heliövaara-Peippo et al. (2011)
RCT of LNG-IUS vs hysterectomy in women with HMB with 10-year follow-up, primary outcome HRQoL
Both treatments had no effect on blood lipids, but there was an increase in serum inflammatory markers (such as high sensitivity CRP) in the hysterectomy group
Ng et al. (2009)
RCT of LNG-IUS vs copper IUD on lipid metabolism
LNG-IUS user was associated with no adverse effects on lipid metabolism
Morin-Papunen et al. (2008)
Population-based study of LNG-IUS vs OC and no hormonal contraceptive users on CVD risk markers & insulin sensitivity
LNG-IUS use was not associated with adverse effects on blood pressure, lipid profile, CRP levels or insulin sensitivity, compared with users of nonhormonal contraception
Kayikcioglu et al. (2006)
Prospective study in LNG-IUS users with HMB on CVD risk markers and metabolic parameters
LNG-IUS was associated with no adverse effects on lipid metabolism or liver function tests. Diastolic blood pressure decreased, fasting glucose significantly increased
Lidegaard et al. (2012)
VTE
Registry-based epidemiological study on first-time VTE in users of non-oral contraceptive methods, compared with nonhormonal method users
LNG-IUS use was associated with a significantly decreased risk of VTE, compared with nonhormonal method use
Lidegaard et al. Arterial thrombosis Registry-based epidemiological study on stroke LNG-IUS use was not associated with an increased risk of stroke or
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(2012) and myocardial infarction in users of various contraceptive methods, compared with nonhormonal method users
myocardial infarction, compared with nonhormonal method use
Lessard et al. (2008)
Vaginal flora and cervical cytology
Prospective study on cervical cytology and vaginal flora in long-term LNG-IUS users
No increase in cytopathological abnormalities, BV or Trichomonas vaginalis incidence
Neale et al. (2009)
Prospective comparison of vaginal smears of LNG-IUS users an copper IUD users
Copper-releasing IUD users were more likely than LNG-IUS users to have abnormal vaginal flora and BV
Donders et al. (2011)
Prospective study on cervical cytology in LNG-IUS users
Occurrence of abnormal vaginal flora, BV, aerobic vaginitis or Candida vaginitis not increased compared to preinsertion
Kaliterna et al. (2011)
Comparison of IUCD users vs noncontraceptorsEscherichia coli and Ureaplasma urealyticum more often isolated from IUCD users than noncontraceptive method users
van Grootheest et al. (2011)
Uterine perforation Retrospective case series of uterine perforations
Abdominal pain and control visit were the most common reasons leading to diagnosis of uterine perforation. Uterine perforation may be asymptomatic and remain undetected
Kaislasuo et al. (2012)
Population-based study on uterine perforations treated surgically in Finland
Estimated perforation rate with both copper IUDs and LNG-IUS was 0.4/1000 insertions. More than half of women who experienced perforation had delivered within 6 months and one out of three were breast-feeding at time of placement
Merki-Feld et al. (2008)
Expulsion Retrospective analysis of clinical records of LNG-IUS and copper IUD users
Lower risk of device dislocation was observed in LNG-IUS users, compared with copper IUD users. History of expulsion was associated with higher risk of re-expulsion
Bahamondes et al. (2011)
Prospective comparison of LNG-IUS and copper IUD users
Expulsion rates were in 2.2% of LNG-IUS users and 5.5% of copper IUD users
Skrzypulec and Drosdzol (2008)
Sexual function Cross-sectional analysis of LNG-IUS and copper IUD users using FSFI
Prevalence of female sexual dysfunction was lower among LNG-IUS vs copper IUD users
Witting et al. (2008)
Epidemiological study of FSFI in a population sample
LNG-IUS was associated with less pain, more desire, arousal, satisfaction, compared with other contraceptive methods
Halmesmäki et al. (2007)
RCT of LNG-IUS vs hysterectomy in women with HMB
McCoy scale in LNG-IUS users showed no change over 5 years with the exception of deterioration of satisfaction with partner
Bastianelli et al. (2011)
Single-group prospective study of LNG-IUS users
FSFI score showed improvement in desire and pain, while other domains remained unchanged
Enzlin et al. Cross-sectional study of LNG-IUS and copper LNG-IUS users had similar psychological and sexual functioning
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(2012) IUD users using the short sexual functioning scale
compared with copper IUD users. Overall, the influence of IUCD on sexual functioning was small
Study design Population Results Strengths Weaknesses Quality
Tasci, 2008
New evidence
Prospective observational study
Location: Turkey
Age range: 32-53
Follow-up time: 12 months
46 women with menorrhagia who had completed their families and had no contraindications to using the IUD
Hemoglobin:
At 12 months mean hemoglobin level increased 2.09±1.97 g/dL (p=0.000)
Baseline hb: 11.13±1.61
12 months: 13.22±1.50
Mean increase in hematocrit 3.98±5.6
Amenorrhea:
67.4% (n=31) developed amenorrhea or hypomenhorrhea at 1 year
Fibroids:
In 25 fibroid cases (54%) 20 women saw a decrease in myoma volume (p=0.04, negative difference: n=20)
Adequate follow-up time
Measurement of hormones
Prospective
No loss to follow-up
Small sample size
No comparison group
Doesn’t define menorrhagia
Did not report side effects
II-3, poor
Chattopdhyay, 2011
New
Prospective observational study
42 women age 35-55 with menorrhagia and without organic pelvic pathology
PBAC:
Significant reduction in PBAC after 3 months (p<0.001) and continued reductions through 36 months
Prospective
Detailed inclusion/exclus
Large loss to follow-up
No side effects
II-3, poor
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evidence Location: India
Age range: 35-55
Follow-up time: 36 months
Dysmenorrhea:
85% of patients were relieved of dysmenorrhea by month 3 and the rest at 6 months
Amenorrhea:
40.74% of patients had amenorrhea by 1 year, however 2.63% had heavy bleeding at the end of 6 months
Hb levels:
Significant improvement (p<0.001), maximum improvement seen at 12 months from mean 9.8 to 12.13
ion criteria
Objective measurement of menorrhagia
Adequate follow-up time
reported
Small sample size
Little information on drop outs
No comparison group
Desai, 2012
New evidence
Prospective observational study
Location: India
Age range: 41-50
Follow-up time:
40 women age 41-50 with menorrhagia due to benign causes
Menstrual pattern:
At 3 months:
7.5% (n=3) had regular cycles
60% (n=24) had spotting
12.5% (n=5) had infrequent cycles with scanty menstruation
20% (n=8) had HMB
Prospective
Detailed description of continuations
Detailed inclusion/exclus
Small sample size
No comparison group
No side effects reported
II-3, poor
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12 months
At 6 months
32.5% (n=13) had spotting
27.5% (n=11) had infrequent cycles with scanty menses
22.5% (n=9) had amenorrhea
7.5% (n=3) had HMB
At 12 months
32.5% (n=13) were spotting
27.5% (n=11) had infrequent cycles with scanty menses
22.5% (n=9) had amenorrhea
Expulsions and removals:
4 IUDs (10%) were expelled with clots within 6 months
ion criteria
Data relies on self-report
Older age range
Endrikat, 2009
New
Randomized control trial
LNG-IUS: 20 women—only
39 healthy women with menorrhagia.
PBAC:
MBL w/IUS declined significantly from baseline to 12 months (p<0.001).
LNG-IUS median score decreased from
Defines menorrhagia
Detailed inclusion/exclus
Small sample size
II-3, good
Only grading on LNG-IUS
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evidence reporting this arm
Oral contraceptive: 19 women
Location: Canada
Age range: over 30
Follow-up time: 12 months
228 to 13 (mean change 83%)
Hemoglobin:
Significant increase (p<0.001).
LNG-IUS mean increase from 126 to 134 g/L at 12 months.
Menorrhagia severity:
Decreased severity in every group
At 6 months LNG-IUS significantly lower (p=0.045)
Adverse effects:
1 person in LNG-IUS had an inguinal hernia that was considered non-treatment related.
ion criteria
Prospective
Randomized
Side effects and adverse effects reported
Adequate follow-up time
arm
Goni, 2009
New evidence
Prospective observational study
Location: Spain
82 women with idiopathic menorrhagia that were indicated to have a hysterectomy but inserted an LNG-IUS instead
Duration of cycle:
Increased from 26.9 to 52.6 days by 12 months (p<0.0001)
Number of days of bleeding per cycle:
Decreased from 8.9 to 5.0 days by 12
Prospective
Defines menorrhagia
Detailed
Bleeding measured by self-report
No comparison group
II-3, good
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Age range: mean 44.3
Follow-up time: 12 months
months (p<0.0001)
Number of sanitary measures:
Decreased from 29.3 to 8.1 by 12 months (p<0.0001)
Intensity of bleeding:
98.8% reported intense bleeding at baseline to 6.4% by 12 months. 81.0% reported no or scarce bleeding by 12 months and 86.9% reported no limitations in daily activities. After 1 year 15.9% of women developed amenorrhea
Hemoglobin:
Increased from 11.0 to 13.0 g/dl at 1 year (p<0.0001)
Ferritin:
Increased from 17.4 to 43.6 ng/ml at 1 year (p<0.0001)
inclusion/exclusion criteria
Large sample size
Adequate follow-up time
Adverse effects and side effects reported
Detailed description of women who discontinued the LNG-IUS
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Expulsion (n=3)
Gorgen, 2008
New evidence
Prospective observational study
Location: Turkey
Age range: 26-55
Follow up-time: 6 months
66 premenopausal women who had sought care in the previous year for menorrhagia
PBAC:
Significantly decreased (p<0.001) from mean 150.88 to 38.95 by 6 months, a 74% decrease
Adverse effects:
46.6% reported no adverse effects. 16.7% had spotting and 13.3% had pelvic pain
VAS scores:
-Pelvic pain: decreased from 4.32 to 3.55 (p=0.024)
Detailed inclusion/exclusion criteria
Adverse effects reported
Prospective
No definition of menorrhagia
Short follow-up time
No confirmation of medical records
No comparison group
II-3, very poor
Gupta, 2006
New evidence
Prospective cohort study
Groups:
LNG-IUS: 25 women—only reporting on this arm
50 healthy women with a PBAC score of 100 or greater who had been unresponsive to oral or injectable hormonal and nonhormonal treatment for at least 1 year
PBAC:
Reduction at 12 months, 98.6% for LNG-IUS
From 463.86 in LNG-IUS to 14.53
Hemoglobin levels:
Significant increase in levels at 6 and 12 months (p=0.024),
Comparative study—1st to compare LNG-IUS with TCRE in developing country
Detailed inclusion/exclusion criteria
Small sample size
No discussion of confounding
Homogenous population
II-3, fair
Only grading on LNG-IUS arm
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TCRE: 25 women
Location: India
Age Range: mean 39.24
Follow-up time: 12 months
At 12 months concentrations increased by 5.5% in LNG-IUS group (from 11.60 to 12.24 g/dL in LNG-IUS)
Expulsions:
2 expulsions
Confirmation of menorrhagia (PBAC score > 100) among participants prior to entry into study
Detailed drop-out information
Gupta, 2013
New evidence
Randomized control trial
Groups:
LNG-IUS: 285 women
Other medical treatments: 286 women
Location: United
571 women with menorrhagia reported in at least 3 consecutive menstrual cycles
MMAS:
Improved significantly by 13.4 points over 2 years
Benefit of LNG-IUS greater in women with BMI>25 (p<0.001)
Serious adverse events:
49 events in LNG-IUS group. 1 death in LNG-IUS group unrelated to treatment
Large sample size
Long follow-up time
Detailed inclusion/exclusion criteria
MMAS data from self-report
Treatments could be switched if patient desired, and a large number of women did switch
Number of adverse events reported but no
II-3, very poor
Only grading on LNG-IUS arm
18
Kingdom
Age Range: 25-50
Follow-up time: 24 months
description
No definition of serious adverse events
Koh, 2006
New evidence
Prospective observational study
Location: Singapore
Age range: 30-49
Follow-up time: 6 months
41 healthy, parous women with menorrhagia (PBAC > 100) for at least 2 consecutive cycles before the study
MBL:
Menorrhagia reduced 61% (26/41) by 1st month, 88% (35/41) at 3 months and 100% (41/41) after 6 months.
At 6 months 39% (16/41) women became amenorrhoeic
Hb and hematocrit:
Increase in Hb from 117 g/L at baseline to 136. (p=0.01)Hematocrit increased from 0.37 to 0.40 at 6 months (p=0.05)
Detailed inclusion/exclusion criteria
Confirmation of menorrhagia (PBAC score> 100) among participants prior to study entry
Detailed outcome measurements
Sparse data on characteristics of populations, aside from outcome measurements
Small sample size
Short follow-up time
II-3, fair
Lee, 2013
New
Prospective cohort study
647 healthy women age 18-45 diagnosed with HMB
Bleeding pattern:
LNG-IUS by 12 months:
-Number of bleeding days reduced by
Detailed inclusion/exclusion criteria
Imbalanced populations in groups
II-3, poor
Only grading on
19
evidence Groups:
LNG-IUS: 483 women
Conventional Medical Therapies: 164 women
Location: Various clinics in China, Taiwan, Hong Kong, Indonesia, Malaysia, Pakistan, Korea, and Thailand
Age range: 18-45
Follow-up time: 12 months
mean 4.0 days
-Number of spotting days reduced by mean 0.3 days
-Dysmenorrhea remission in 76.1% of women (n=363)
-PMS resolved in 77.6% of women (n=337)
-HMB persisted in 2.1% of women (n=10)
Adverse effects:
4.6% device related complications (17 expulsions, 2 dislocations, and 1 breakage)
Comparison group
Large sample size
Adverse events reported
No definition of menorrhagia
Outcomes based on “validated” patient questionnaire—no explanation of what this means
Widespread population, no knowledge of how clinics diagnose menorrhagia
LNG-IUS arm
Lete, 2008
New
Prospective observational study
225 women with idiopathic menorrhagia
Bleeding:
-Cycle length: increased from 26.16 days at baseline to 29.17 days at 1 year (p=0.0077)
Large sample size
Adequate
No definition of menorrhagia
Data based on
II-3, poor
20
evidence Location: Spain
Age range: mean 43.13
Follow-up time: 12 months
-Number of sanitary products: decreased from 30.34 to 8.97 at 1 year (p<0.0001)
-Number of bleeding days: decreased from 7.60 to 4.69 at 1 year (p<0.0001)
Hb and S-Fe:
Increase in hb from 11.72 to 13.33 g/dL and increase in ferritin from 16.73 to 42.70 ng/mL at 1 year
follow-up time
Prospective
Adverse events reported
self-report
No comparison group
No inclusion/exclusion criteria reported
Malgalhaes, 2007
New evidence
Prospective cohort
Groups:
LNG-IUS for women with idiopathic menorrhagia (n=32)
LNG-IUS for women with menorrhagia due to uterine leiomyomas (n=27)
87 women with menorrhagia
Conducted in private gynecological clinic
Excluded women with history of PID in preceding 2 years and those at risk or with previous history of STIs
Menstrual bleeding patterns:
After 36 months amenorrhea and oligomenorrhea were most frequent patterns, occurring in 45-57% and 33-39% of users in 3 groups, respectively; amenorrhea was higher in contraception group (57.1%) and in women with idiopathic menorrhagia (53.4%) than women in group with menorrhagia due to leiomyomas (44.5%) (p=0.27)
Prevalence of spotting approx. 3 times higher (11%) in women with menorrhagia caused by leiomyomas and nearly double (7.7%) in women with idiopathic menorrhagia compared with control group (4%) p=0.24
Detailed inclusion/exclusion criteria; detailed measurement assessments of criteria
Comparative study with control group
Detailed follow-up
Lack of measurement of menorrhagia
Homogenous population
No discussion of confounding
II-3, fair
Only grading on idiopathic menorrhagia arm
21
LNG-IUS for women desiring contraception (n=28)
Location: Brazil
Age range: 21-51
Follow-up time: 36 months
Sesti, 2012
New evidence
Randomized control trial
Groups:
LNG-IUS: 36 women
LSH: 36 women
LSH:
72 healthy premenopausal women with menorrhagia that was unresponsive to other medical treatment and had no desire for more children
PBAC:
Significantly reduced
Bleeding patterns:
-Spotting: At 24 months 5 women in LNG-IUS group (13.9%) reported spotting
-Amenorrhea: At 24 months 1 (2.8%) LNG-IUS woman was amenorrhoeic.
-LNG-IUS group had significant improvement in bleeding frequency and length (p=0.000) at 3 and 6 months. At 12
Detailed inclusion/exclusion criteria
Detailed operation procedure
Adequate follow-up time
Some data from self-report
II-3, good
Only grading on LNG-IUS arm
22
Laparoscopic supracervical hysterectomy
Location: Italy
Age range: 35-50
Follow-up time: 24 months
months 10 women (27.8%) reported an even more reduced bleeding frequency and length. At 24 months patients reported an increased bleeding frequency and length from 3 months. (p=0.000)
Hb:
Both groups were significantly improved. At 3, 6, 12, and 24 months LSH group had more significant improvement
Defines menorrhagia
Silva-Filho, 2012
New evidence
Prospective randomized control trial
Groups:
LNG-IUS. 30 women
TBA: 28 women
TBS: thermal balloon ablation
58 healthy women with menorrhagia that has been unresponsive to other treatment
Five year follow-up of treatment
Hb:
LNG-IUS hb increased from 12.5±0.3 to 14.41±0.3 g/dL (p=0.0056)
Bleeding pattern:
-LNG-IUS associated with less MBL after 5 years (p=0.001)
-LNG-IUS: No patients had increased MBL and 35.3% had amenorrhea
Detailed inclusion/exclusion criteria
Detailed treatment methods
Accounts for development of menopause
No adverse effects reported
Data relies on patient self-report
II-3, fair
Only grading on LNG-IUS arm
23
Location: Brazil
Age range: Over 35
Follow-up time: 5 years (follow-up of previous study)
Shabaan, 2011
New evidence
Prospective randomized control trial
Groups:
LNG-IUS : 56 women—only reporting on this arm
COC: 56 women
Location: Egypt
112 women complaining of excessive menstruation
Expulsions:
1 expulsion
Menstrual blood loss:
Reduction significantly higher at 12 months in LNG-IUS group (p=0.013) with alkaline hematin method
MBL reduced from 300 mL at baseline to 44.4 mL at 12 months for LNG-IUS group
PBAC reductions significantly higher in LNG-IUS group at 12 months (p<0.001)
Detailed exclusion criteria
Small loss to follow-up
Objective measurement of blood loss
Menorrhagia not confirmed by a physician and not defined
Measured hemoglobin and serum ferritin but did not report on them
No report on adverse effects
II-3, poor
Only grading on LNG-IUS arm
24
Age range: 20-50
Follow-up time: 12 months
Kaunitz, 2010
and
Kaunitz, 2012
(follow-up to 2010 study)
New evidence
Randomized control trial
Groups:
LNG-IUS: 82 women—only following this arm
Oral medroxyprogesterone acetate: 83 women
Location: USA
Age range: over
165 women with idiopathic heavy menstrual bleeding, 80 mL blood loss or more per cycle
MBL:
Significantly greater reductions in LNG-IUS group. 80% of women experience a 70% decrease by 6 months
Average decrease 128.8 mL
Adverse effects:
No deaths or serious adverse effects
2 partial expulsions
2 full expulsions
Hemoglobin levels:
Increased from 12.4 g/dL to 13.4
Defines menorrhagia
Detailed exclusion criteria
Reported adverse effects
Short follow-up time
II-3, good
25
18
Follow-up time: 6 months
Serum ferritin:
Increased from 19.0 mcg/L to 34.0
Palmara, 2013
New evidence
Prospective observational study
Location: Italy
Age range: 29-44 (premenopausal)
Follow-up time: 12 months
40 women, 24 premenopausal and 16 postmenopausal. The 24 women had idiopathic AUB or endometrial hyperplasia
Only reporting on premenopausal women
Efficacy:
For fertile women, at 6 months 72.7% (n=16) reported a regular menstrual cycle and 13.6% (n=3) reported intermenstrual spotting. 13.6% (n=3) of women reported amenorrhea
At 12 months 68.2% (n=15) reported regular menstrual cycle and 0 women reported intermenstrual spotting. 31.8% (n=7) reported amenorrhea.
Adequate follow-up time
Small sample size
No comparison group
Menorrhagia not defined
Side effects not reported
Includes postmenopausal women
II-3, very poor
Kriplani, 2007
New
Prospective observational study
63 Indian women age 29-52 with idiopathic menorrhagia or menorrhagia due to uterine fibroids
Expulsion:
Expelled in 6 patients (9.5%), twice in 2 patients
Detailed exclusion criteria
Very little description of patients’ symptoms before
II-3, good
26
evidence Location: India
Age range: 29-52
Follow-up time: 36 months
Menstrual blood loss:
3 months: menorrhagia cured in 35 patients (77.7%)
36 months: cured in all patients
By 1 month: Significant decrease in mean number of bleeding days (p=0.01) and mean PBAC score (p=0.00) and further reductions as time went on
18 patients developed amenorrhea (28.6%)
Dysmenorrhea:
Completely relieved in 31 of 40 patients (77.5%) at 3 months
At 24 months no dysmenorrhea in any patient
Hemoglobin levels:
Significant mean increase (1.06±1.7 gm/dL, p=0.000) by 12 months
Objective measurement of blood loss
intervention
No definition of menorrhagia
27
Outcome in patients with fibroids:
25 patients had fibroids. 3 (12%) developed menorrhagia, 10 (40%) had intermenstrual spotting that stopped between 3 and 6 months
3 expulsions (12%)
Shaw, 2007
New evidence
Randomized control trial
33 women randomized to TBA
33 women randomized to LNG-IUS—only recording LNG-IUS arm
Location: United Kingdom
Age range: 25-49
66 women with idiopathic menorrhagia for whom oral medication had failed
PBAC:
Significant decrease in median scores during 12 months of follow up (p<0.001)
At 9 and 12 months no patient had a PBAC score greater than 120
Hb and serum ferritin:
Hb levels rose by 6 months from 12.1±1.7 g/dL to 12.8±.6
Serum ferritin levels rose by 6 months from 18.4±10.1 mg/L to 19.8±9.7
Bleeding patterns:
6 of 23 patients had amenorrhea at 12 months (26%)
At 3 and 6 months median number of days
Defines menorrhagia
Detailed inclusion and exclusion criteria
Hb and serum ferritin not reported at 12 months
I, fair
28
Follow-up time: 12 months
of bleeding was 14.6
At 9 and 12 months median number of days of bleeding was 4.2
De Souza, 2010
New evidence
Randomized control trial
LNG-IUS: 30 women—only reporting on this arm
TBA: 28 women
Location: Brazil
Age range: mean 41.9
Follow-up time: 12 months
58 women with idiopathic menorrhagia
Hb levels:
Significant increase by 12 months (p<0.001)
Menstrual blood loss:
Significant reduction in blood loss by 12 months (p<0.001)
Menorrhagia confirmed by objective testing
Very little data provided
Baseline characteristics reported poorly
II-3, very poor
Only grading on LNG-IUS arm
Ghazizadeh, 2011
Randomized control trial
104 women age 35-45 with menorrhagia
PBAC:
Significantly decreased at 6 and 12 months
Detailed inclusion and exclusion
Mixed population of women suffering from
II-3, fair
29
New evidence
LNG-IUS: 52 women—only reporting on LNG-IUS group
TCRE: 52 women
Location: Iran
Age range: 35-45
Follow-up time: 12 months
(p<0.0001)
Score at 6 months was 60.38±110.65
Amenorrhea:
11.1%
Spotting:
6 patients (12.7) reported spotting
Expulsions:
9 patients
criteria menorrhagia caused by different medical conditions
Only grading on LNG-IUS arm
Theodoridis, 2009
New evidence
Non-randomized control trial
LNG-IUS: 42 women—only reporting on this arm
Endometrial
79 Greek women with idiopathic menorrhagia
Duration of uterine bleeding:
Baseline: 6.8 days
6 months: 2.7 days
12 months: 2.2 days
Very little data II-3, very poor
30
thermal rollerball ablation: 37 women
Location: Greece
Age range: mean 37.3
Follow-up time: 12 months
Yazbeck, 2006
New evidence
Prospective observational study
1999 – 2000
10 centers in France
Age range: mean 43 ± 5.3 years
52 women presenting with menorrhagia resistant to treatment without contraindications for LNG-IUD use
Data available: 42 at 6 months; 40 at 12 months; 20 at 24 months & 14 women at 3 years
Four patients discontinued LNG-IUS and had surgery during 1st year.
PBAC Score
Score declined from 254.0 to 23.5 from baseline to 6 months. 36 (86.7%) women experienced at least ≥ 60% decline in PBAC score in first 6 months. Score stabilized between 6-12 months.
Clear inclusion and exclusion criteria
Prospective evaluation
Provided power calculation
Loss to follow up during all periods
Needed 52 women to demonstrate benefit of avoiding surgery, but only 42 women with data at 12 months
II-3, fair
31
Follow-up time:
36 months
Hemoglobin (g/dl)
Baseline mean: 12.9±1.3
12 months: 14.0±1.1, p<0.001
Ferritin (ng/ml)
Baseline mean: 27.4±25.5
12 months: 45.4±27.3, p<0.01
Dysmenorrhea
Baseline: n=25/44 (56.8%)
6 months: n=5/40 (12.5%)
12 months: n=5/32 (15.6%), p<0.001
Tam, 2006
New evidence
Randomized control trial
LNG-IUS: 22 women—only following this arm
44 women with menorrhagia that failed to respond to conventional medical therapy
Bleeding pattern:
5 women (33.3%) remained menorrhagic
0 women had amenorrhea
2 women had spotting (13.3%)
4 women had hypomenorrhea (26.7%)
Adequate follow-up time
No confirmed diagnosis of menorrhagia
Small sample size
II-3, very poor
32
Thermal balloon endometrial ablation: 22 women
Location: Hong Kong
Age range: Over 40
Follow-up time: 12 months
4 women had normal bleeding (26.7%)
Expulsions:
2 expulsions (11%)
Hemoglobin levels:
Significant improvement at 12 months
From 9.3 g/dL to 10.3
No definition of menorrhagia
No objective measurement of bleeding
No description of how bleeding was measured
No follow-up appointments before 1 year
Busfield
2006
Design
Randomized comparative trial
2 Groups:
LNG IUS: 42 women
Characteristics
42 women in the LNG-IUS group with the age distributions: 16.7% less than 40 years, 50.0% between 40 and 44 years, and 33.3% between 45 and 49 years, with self-described heavy menstrual bleeding, and did not have any
54.8% of participants had undergone sterilization or vasectomy, thus a large percentage of the study population did not use this method for contraceptive
II-3, fair
33
Thermal Balloon Ablation (TBA): 41 women
Location
New Zealand
Follow-up
24 months
ultrasound, laboratory or hysteroscopic abonormalities.
Decrease from baseline to follow-up (which plateau)
purposes
Did not account for possible onset of menopause during trial
No objective measure of ‘heavy bleeding’ provided
34
Baseline: 3.8 (2.0) 3 months*: .4 (1.0)
12 months: .5 (1.3) 24 months: .3 (.8)
Reid
2005
Design
Randomized comparative trial
2 Groups:
LNG IUS
Mefenamic acid
Location
United Kingdom
Follow-up
6 cycles
Dates
May 1996- December 1998
Characteristics
51 women with a mean age of 39.4±4.4 years in the LNG IUS group and 38.5±4.2 years in the mefenamic acid group with objectively proven idiopathic uterine bleeding (menstrual blood loss of ≥ 80 mL)
Initial Distribution
LNG IUS: 25
Mefenamic acid: 26
0 Lost to follow-up
Discontinuations (n=4)
Partial expulsions: 2
Complete expulsion: 2
Median Menstrual Blood Loss
(significant difference between each time period p<.005)
Baseline: 122 (81-375)
Cycle 3: 12 (0-240)
Cycle 6: 5 (0-45)
Total Menstrual Fluid Loss
(significant difference between each time period p<.005)
Baseline: 183 (103-527)
Cycle 3: 53 (0-459)
Objective confirmation of menorrhagia among participants prior to entrance in to study
Sparse baseline characteristics of participants provided
II-3, fair
35
Cycle 6: 27 (0-156)
PBAC Score
(significant difference between each time period p<.005)
Baseline: 240 (91-545)
Cycle 3: 49 (0-286)
Cycle 6: 25 (0-402)
2 serious adverse events:
1) Hypertension (strong family history)
2) Chlamydial Endometritis
Hurskainen
2004
Hurskainen
2001
Design
RCT:
LNG-IUS v hysterectomy
Follow-up
6 months
Characteristics:
236 women
ages 35-49
Complaints of menorrhagia, completed desired family size
Only 58% of study participants had objective menorrhagia according to study criteria (MBL≥80mL)
II-3, fair
36
12 months
5 years
Location
Finland
Dates
10/1/94-10/6/2002
Distribution
119 LNG-IUS
117 Hysterectomy
Mean MBL
only 4 had enough bleeding pattern to submit samples at 5 years
baseline: 130mL ± 116
follow-up: 17mL ± 11.3
Range: 8-32mL
Hemoglobin & Serum Ferritin Levels
Significant increase in blood hemoglobin & serum ferritin concentrations
Radesic
2004
Design
Descriptive study
Location
New Zealand
Dates
June 1998- June 2002
Characteristics:
78 women
(ages n/a)
who had an LNG-IUS inserted at Palmerston North Hospital for the treatment of Dysfunctional Uterine Bleeding (99% for regular or irregular heavy periods)
1 expulsion (but subsequent reinsertion)
Overall improvement: 78%
61 reported lighter or no periods
23 minimal spotting
21 amenorrhoeic
8 heavy/irregular bleeding
2 heavier
Dysmenorrhea:
Standardized measurements
Non-standardized insertion
65% response rate
II-3, good
37
3 increased 9 unchanged menstrual pain
57 subjectively significant improvement
Rauramo 2004
Istre 2001
Design
Open RCT:
LNG-IUS v endometrial resection
Follow-up
6 weeks; 6, 12, and 36 months
Location
Norway
Enrollment Dates
3/24/93-10/12/95
Characteristics:
59 women
Ages 30-49 years (mean: 41.4 ± 3.8 years)
With idiopathic menorrhagia, a regular uterine cavity ≤ 10 cm long, who are pre-menopausal and no wish for further pregnancy
Distribution:
30 L-IUD
29 transcervical endometrial resection (TCRE)
At 36-month follow-up:
MBL
PBAC results:
showed significant decrease (p=.001)
Baseline: 261.5 (60-1503)
Follow-up: 7.0 (0-101)
MBL < 60mL not achieved in 3 women
Blood Hemoglobin & Serum Ferritin
Significant increase in concentration (p=.001)
Bleeding Days
Significant decrease p<.001
Baseline: 25 Follow-up: 0
Significant decrease in median # days spotting; p<.001
Baseline: 22 days Follow-up: 1 day
Standardized measures & methodology
Appropriate follow-up time
Detailed information for both 12-month and 36-month follow-ups
Low follow-up rate (63.3%)
No power information provided
No information on drop-outs provided after 12 months
II-3, good
38
Amenorrhea
Baseline: 0 women Follow-up: 6 women
Menstrual Pain
Significant decrease in # days with mild pain from baseline to 36 months (p=.001)
Significant decrease in # days with moderate/severe pain from baseline to 36 months (p=.001)
Adverse Effects
1 case of edema 3 endometriosis
2 PID 1 partial expulsion
1 partial expulsion
Barrington
2003
Design
RCT:
LNG-IUS v Endometrial Thermal Ablation (ETA)
Characteristics:
50 women
(ages not given) with
menorrhagia refractory
LNG-IUS Group
Amenorrhoeic: 3
PBAC: 16 improved
Baseline characteristics of population not provided
II-3, fair
39
Follow-up
6 months
Location
England
to medical therapy
Distribution:
25 LNG-IUS
25 ETA
2 unchanged
(pre mean =107, pre median= 75, post mean =31, post median= 19)
Small sample size
p-values within groups not provided
Xiao
2003
Design
Prospective study
Follow-up
every 3 months for 36 months
Location China
Dates
Initiated: 1996
Characteristics:
34 parous women 27-34 years of age (mean: 35 ± 4.4 years) who experienced regular or heavy menstrual bleeding with a normal sized or slightly enlarged uterus with an average menstrual blood loss (MBL) over 80ml and failure in previous treatments with hormones or traditional medicine
Lost to follow-up: 2
Expulsions: 4
2 complete 2 partial
Length of spotting
Range: 30 to 90 days, Median: 42 days
Hb Concentrations g/L
significant increase from baseline to each follow-up (3, 6, 12, 24 and 36 months): p<.0001
mean range: 121.5 to 138.7
Good length of Follow-up time
Standardized methods of measuring
Recruitment information missing
II-3, good
40
Serum Ferritin
significant increase from baseline to each follow-up (3, 6, 12, 24 and 36 months): p<.0001
mean range: 21.9 to 92.8
Bleeding Trends:
Alternating between amenorrhea and spotting
Increasing time correlated with increasing amenorrhea rates
MBL
Average Reduction: 86.3%
Baseline: 124.2mL, 6 to 36 months ranged from 26.4 to 2.7 mL.
(78.7% to 97.7% reduction range)
Change in MBL:
Over 1/3 amenorrhoeic
41
¼ scanty spotting
Henshaw
2002
Design
Retrospective cohort study
2 groups:
LNG-IUD
and
Microwave endometrial ablation (MEA)
Location Australia
Follow-up
for LNG-IUD group:
20.9 ± 12.6 months
Dates
1998-2001
LNG-IUD Characteristics:
55 women
(aged 36.8 ± 9.8 years in LNG-IUD group and 41.3 ± 7.7 years in MEA group)
with either hospital records or treating specialists’ medical records indicating treatment for heavy menstrual loss using either LNG-IUD or MEA between 1998 and 2001
Initial Distribution:
LNG-IUD: 23
MEA: 39
Mean Bleeding Score:
Significant change (p<.0001)
pre-treatment: 30.7 post-treatment: 8.2
Mean Dysmenorrhea Score:
Significant change (p<.0025)
pre-treatment: 13.2 post-treatment: 6.2
Study design
Non-standardized measures
Necessary sample size not mentioned
II-3, fair
42
Monteiro
2002
Design
Descriptive prospective non-comparative study
Follow-up
3, 6, 9 and 12 months
Location Brazil
Dates
3/99-12/03
Characteristics:
44 women
ages 22 to 49
who were on waiting lists for hysterectomy or endometrial ablation for menorrhagia after unsuccessful medical treatment
At 12 Months:
-6 expulsions
Hb concentration (g/L):
improved in all patients
significant change from 102 ± 14 to 128 ± 19 (p<.01)
Bleeding Patterns
Trend:
3 months:
over 60% spotting
abnormal uterine bleeding not well controlled
2 complained of Menorrhagia
6-12 months:
(at 12 months, 35 remaining women)
amenorrhea most frequent
Amenorrhea: 21 Oligomenorrhea: 8
Spotting: 4 Normal: 2
Frequent follow-ups
standardized measures
limited population
generalizability
high expulsion rate
II-3, fair
43
Nagrani
2002
Barrington
1997
Design
Prospective study
Location
South Wales
Follow-up:
3 months, between 6 and 9 months, between 4 and 5 years
(mean follow-up time: 54.2 months)
Dates:
1995-1996
Characteristics:
50 women
aged 28 to 53 years who failed to respond to a combination of antiprostaglandins and antifibrinolytics who were awaiting surgical treatment in form of endometrial ablation or hysterectomy
3 months:42 women
6 spontaneous expulsions (4 re-insertions)
Bleeding Patterns
5 sig. reduction in menstrual scores
reduction in clots & flooding
Dysmenorrhea
80% improvement
Ferritin Level:
no significant change (p=.1133; 95% CI:-15.99 to -.01)
4 to 5 years: 23 women remaining, 23 dropouts
5 spontaneous expulsions (2 re-insertions)
Considered uterine cavity length of participants
High loss to follow-up
Non-standardized and non- participant friendly data measures regarding mean blood loss
Characteristics of those who declined to participate were not provided
Older age range of participants (menopausal possibility)
II-3, poor
44
Bleeding Patterns:
Amenorrhea: 8 (34.78%)
Occasional: 13 (56.52 %)
Regular cyclical: 2 (8.69%)
Soysal
2002
Design
Open, parallel group RCT:
LNG-IUD
v
Thermal Balloon Ablation (TBA)
Location
Turkey
Follow-up
3, 6 and 12 months
Dates
10/99 – 11/01
LNG-IUD Group Characteristics:
36 women
aged 43.8 ± 2.7 years with no further desire for childbearing, complaining of dysfunctional menorrhagia who refused or not responded to medical treatment
Distribution:
36 LNG-IUD
36 TBA
Mean PBAC scores
Significantly lower at 12 months
(408 ± 101 to 55.0 ± 11, p-value: <.0001)
-77% successful cases (as defined by PBAC score of ≤ 75)
