Safety and Efficacy of the Levonorgestrel-releasing Intrauterine System

Recent Insights

Kristina Gemzell-Danielsson; Pirjo Inki; Oskari Heikinheimo

Disclosures

Expert Rev of Obstet Gynecol. 2013;8(3):235-247. 

In This Article

Results

Cost–Effectiveness of the LNG-IUS When Used for Contraception

Cost–effectiveness and a health economics perspective is a high priority today. Considerable cost savings both from an individual and a wider health economics perspective can be achieved with effective and acceptable contraceptive methods that help to reduce unwanted pregnancy and from improving menstrual-related bleeding problems. Contraceptive efficacy of the LNG-IUS is comparable to that of female sterilization and has been reported to be equal in all age groups.[1] In a review on articles published over the last two decades on various types of IUCDs (including Cu-IUDs, such as Multiload [Merck, NJ, USA], NovaT [Bayer, Leverkusen, Germany], ParaGard T-380A [Duramed Pharmaceuticals, Inc., NJ, USA] and the LNG-IUS), excellent effectiveness of IUCDs with a global cumulative pregnancy rate of <2% after 5 years of use was observed whatever the type of device.[1] However, the LNG-IUS was the most effective with a cumulative pregnancy rate at 5 years of <0.5%.[1] Higher effectiveness of LARCs in real-life use, regardless of age and other user characteristics, compared with the contraceptive pill, patch or ring, was also confirmed in a recent cohort study from the USA.[2] In the USA, the number of women undergoing surgical sterilization has been reduced due to the introduction of LNG-IUS.[8] High efficacy (no pregnancies) and high level of user satisfaction (84%) were also reported in a prospective clinical study including 509 women over 12 months of use in the USA.[9] Primary reasons for premature discontinuation were expulsion (4.5%) and menstrual cycle problems (3.8%).[9]

According to two cost–effectiveness analyses from the UK and Spain (not including costs for potential contraceptive side effects, noncontraceptive benefits and quality of life changes), LARCs are more cost effective than injectables or oral contraceptive pills and condoms after only 1 year of use.[10,11]

Cost–Effectiveness of the LNG-IUS When Used for HMB

Treatment of HMB with the LNG-IUS has been shown to be cost effective in various countries and settings.[12] A systematic review and meta-analysis of clinical outcomes of treatments for HMB showed a similar degree of improvement of health-related quality of life with LNG-IUS compared with first- or second-generation endometrial ablation (EA) techniques.[12] Cost–effectiveness analysis of hysterectomy versus first- and second-generation EA techniques and the LNG-IUS was analyzed in two reviews.[13,14] The few data available suggest that the LNG-IUS is more cost effective than first-generation EA techniques with satisfaction being similar to that of second-generation EA techniques. Limited evidence suggested that hysterectomy is preferable to the LNG-IUS.[12] However, the long-term risk of pelvic floor surgery and urinary incontinence is higher in women treated by hysterectomy than by EA or the LNG-IUS. Although it may be the most cost-effective strategy in some settings, hysterectomy may not be considered an initial or acceptable option for many patients, owing to its invasive nature and higher risk of complications.

Repeat Use of the LNG-IUS

Repeat LNG-IUS use is increasing worldwide on several indications.[15] Insertion of a second consecutive LNG-IUS after 5 years of use of the first LNG-IUS was judged to be easy and associated with no or mild pain in a vast majority of women.[16,17] Of special clinical impact was the finding that the initial irregular bleeding pattern frequently observed with a first LNG-IUS could be avoided if the second LNG-IUS was inserted immediately. This practice also resulted in further reduction of bleeding and spotting and an increased rate of amenorrhea compared with the rate observed during the use of the first LNG-IUS.[18] Interestingly, in the European setting, the highest satisfaction was seen among the women reporting amenorrhea. However, the acceptability of contraception-induced amenorrhea may vary according to cultural and other characteristics of the women.

Mode of Action of LNG-IUS When Used for Contraception or HMB

Quality and sperm penetrability of mid-cycle cervical mucus from LNG-IUS users and hormone-free controls was compared in vitro in a double-blinded fashion.[19] It was shown that mid-cycle cervical mucus of LNG-IUS users was of poor quality and thus prevented endocervical sperm transport, confirming earlier studies that this is the main mechanism of contraceptive action of the LNG-IUS. Thus, the contraceptive action of the LNG-IUS happens before fertilization, which is an important counseling aspect.

The endometrial suppression is responsible for the reduced bleeding and thus the therapeutic effect in treatment of HMB. This is associated with an increase in uterine artery resistance index in LNG-IUS users, which is not observed in Cu-IUD users.[20]

LNG-IUS After Abortion

The safety and efficacy of immediate postabortal placement of the LNG-IUS has earlier been demonstrated by several studies. However, some clinicians may still have concerns over this topic and most previous data refers to early surgical termination of pregnancy. In a recent randomized controlled trial (RCT) comparing immediate versus delayed (3–6 weeks after surgery) placement after elective second trimester pregnancy termination, expulsion rates were similar (6.8 and 5.0%, in the immediate and delayed groups, respectively, p = 1.0), and there were no marked differences in other adverse events, either.[21] However, only 45.5% of the women randomized to delayed insertion actually returned to the placement visit, and thus significantly more women had the LNG-IUS placed in the immediate rather than in the delayed placement groups. This highlights the importance of starting contraception as soon as possible after elective pregnancy termination. Thus, even though the expulsion rate may be somewhat increased (in particular after second trimester abortions), immediate insertion should be encouraged at the time of surgical first or second trimester abortion.[21–23]

There are less studies concerning insertion of IUCD after medical abortion. An ideal time for IUCD placement may be the day a woman presents for verification of a completed medical abortion, which is usually performed at 1–3 weeks after treatment. In earlier studies of IUCD use following medical abortion, the devices have been inserted either at 2–3 weeks after abortion or at the time of first postabortal menstruation.[24] Recently, the Cu-IUD was shown to be inserted in a safe manner during the first week after the medical abortion.[25] The same was shown to be true for the LNG-IUS.[26] Significantly, more women returned for insertion among those scheduled for early insertion to be performed within 1 week of the abortion treatment than those scheduled for delayed insertion at 3 weeks following the abortion. Furthermore, more women with a LNG-IUS reported reduced bleeding postabortion compared with women a Cu-IUD.

The efficacy of IUCD in the prevention of a repeat abortion has been studied in several cohorts and population-based studies.[27–32] All these studies showed that IUCD is more effective in preventing repeat abortions than oral contraception[28,29,32] or other non-intrauterine contraception.[27] Thus, postabortion insertion of IUCD and especially the LNG-IUS seems to be an effective means to avoid repeated unwanted pregnancy and induced abortion.

Is Early Insertion of the LNG-IUS After Delivery Feasible?

The first year postpartum is a period of high risk for unintended pregnancy. Therefore, immediate (within 10 min following delivery of the placenta) postpartal insertion of IUCD has been presented as an option to start effective contraception immediately after delivery. Immediate Cu-IUD insertion has been shown to be safe when compared with later postpartum time periods and interval insertion. For Cu-IUD, increased expulsion rates were noted with delayed postpartum insertion, compared with immediate insertion and with immediate insertion, compared with interval insertion.[33] The placement of the LNG-IUS immediately after delivery has been assessed in four studies.[34–37] In two RCTs, postplacental versus delayed insertion of the device or insertion at three time points, immediate (within 10 min of placenta delivery), early (10 min to 48 h postpartum)[34] or interval (≥6 weeks postpartum),[35] were compared. Expulsion rate was significantly higher in the immediate (postplacental) than in the delayed insertion group; at 6-month follow-up, expulsion had occurred in 12 of 50 versus two of 46 (i.e., 24 vs 4%; p = 0.008) of women in the early and delayed groups, respectively.[35] When lost devices were replaced, the rate of LNG-IUS use observed at 6 months was similar in both groups. This is in agreement with the other RCTs including 46 women; no differences in rates of LNG-IUS at 3 and 6 months were seen between early compared with late insertion groups.[36] Rates of expulsion were significantly higher in the early and immediate groups compared with the interval group. However, pain during insertion was significantly higher in the interval group (p < 0.001) when compared to the other groups.[36] In a case series including 40 women, 29 women received the LNG-IUS at a median of 20 h (range: 7–48 h) after delivery. Eleven women (38%) had a spontaneous expulsion.[31] A pilot study included 20 women and insertion was carried out under ultrasonographic guidance at a median time from placental delivery to insertion of 5.5 min. No perforations were reported. At 10-week follow-up, the expulsion rate was 10.5%.[37]

One RCT reported on the effects of immediate postplacental versus delayed LNG-IUS insertion on the patterns of breast-feeding.[38] Breast-feeding was initiated by 64% (32 out of 50) of the women randomized to immediate versus 58% (27 out of 46) in the group of delayed insertion. However, at 6-month follow-up, significantly, fewer women (6 vs 24%; p = 0.02) in the group of immediate insertion continued breast-feeding.[38] These results are in contrast with the generally viewed safety of progestin-only contraceptive use during lactation as well as previous studies assessing the use of the LNG-IUS during lactation.[39]

Thus, postplacental insertion of the LNG-IUS is a possible option although available studies consistently report increased expulsion rates compared with interval insertion. In addition, more data are needed on the possible impact of LNG-IUS on breast-feeding.

Use of the LNG-IUS in Special Patient Groups

The LNG-IUS has several features, such as reduction in menstrual bleeding and a lower incidence of pelvic inflammatory disease compared with Cu-IUD, which may make it an ideal contraceptive method for women with underlying medical condition(s) such as diabetes mellitus,[40] women living with HIV/AIDS[41] or in women at increased risk of bleeding due to either inherited bleeding disorders[42] or to the use of anticoagulation.[43,44] In these studies, the LNG-IUS has behaved similarly as in healthy women, and has been associated with reduced uterine bleeding, increased blood hemoglobin levels, and most importantly, no effect on the course of the underlying disease.[41]

The use of the LNG-IUS versus no intervention has been compared in a RCT performed in women taking anticoagulant therapy after cardiac valve surgery.[44] Similar to what has been observed in healthy women, vaginal bleeding was reduced and hemoglobin levels increased within 3 months of LNG-IUS use. Coagulation factors were unaffected by the LNG-IUS.[44] Also, when the LNG-IUS is used purely for contraception, it is accompanied with an increase of hemoglobin and ferritin, which may be especially important in women with underlying medical conditions.[45]

Another emerging patient group with special needs are obese women. Use of the LNG-IUS in women with BMI exceeding 30 kg/m2 suffering from abnormal uterine bleeding resulted in reduced menstrual bleeding and high subject satisfaction.[46] In addition, the uptake of the LNG-IUS has been shown to be high in morbidly obese women undergoing bariatric surgery.[47]

New Data Regarding the Safety & Metabolic Effects of the LNG-IUS

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.[48–76] Pregnancy with IUCD or LNG-IUS in situ was analyzed in one review,[48] which reconfirmed the already established medical knowledge that an IUCD left in situ during pregnancy increases various pregnancy complications irrespective of the type of IUCD (Table 1). Removal of the IUCD decreased these risks but not to the expected background frequency of women without an IUCD at the start of pregnancy.

Two studies reported on bone mineral density during the use of the LNG-IUS and neither found a difference between the LNG-IUS and Cu-IUD users.[49,50]

Several studies reported on the cardiovascular disease risk markers and metabolic effects in LNG-IUS users (Table 1). In general, these were consistent with no clinically significant effects (Table 1). Regarding glucose tolerance, one study described slightly increased fasting blood glucose in premenopausal women, however, impaired glucose tolerance was not diagnosed.[55]

Two registry-based studies have analyzed the risk of venous thromboembolism[56] and arterial cardiovascular complications (stroke and myocardial infarction [seven in LNG-IUS users]).[57] Since the exact exposure to LNG-IUS in this study was not known due to the unavailability of information regarding the date of removal, the authors assumed 3-year exposure from the date of prescription. However, this could have led to an underestimation of the actual exposure due to the fact that LNG-IUS is licensed for 5 years of use. Nevertheless, the LNG-IUS was not associated with an increased risk of either venous or arterial thrombotic events (Table 1). In contrast, LNG-IUS use was associated with a significantly decreased risk of venous thromboembolism compared with nonhormonal method users, a finding which, however, lacks biological plausibility as pointed out in the so-called rapid responses to this article.[101]

The effect of LNG-IUS on the vaginal flora and cervical cytology was studied in four publications using different methodologies (Table 1). In general, no increase in the incidence of bacterial vaginosis or cytological abnormalities was found.

Two studies reported on uterine perforation associated with IUCD.[62,63] The first study analyzed spontaneous adverse drug reaction reports, thus the denominator – in this case the number of insertions or women-years is not known, preventing calculation of incidence rates.[62] Only in approximately 40% of reports was information provided regarding symptoms leading to the diagnosis of perforation; the most frequent symptoms being abdominal pain and abnormal bleeding.[62] Of the women known to be parous, approximately 42% were breast-feeding at the time when perforation was diagnosed.[62] Kaislasuo et al. reported the estimated uterine perforation rate of approximately 0.4 per 1000 insertions in a population-based study in Finland, which was similar in the LNG-IUS and Cu-IUD users.[63] A total of 55% of women experiencing uterine perforation had their IUCD placed <6 months after the delivery, and approximately one out of three were breastfeeding at the time of placement. However, it was not possible to calculate the magnitude of the possibly increased risks of uterine perforation in postpartum or breastfeeding women, as the denominator (i.e., total population of women postpartum or breastfeeding) was not known. Importantly, neither publication reported any cases of serious or permanent sequelae from the uterine perforations.

Two studies reported a lower expulsion and/or dislocation rate in LNG-IUS users, compared with Cu-IUD users (Table 1), but the overall expulsion rates were low in both groups, and it is not clear if the studies were sufficiently powered to detect small differences.

In general, LNG-IUS was reported to have a neutral effect on sexual function although one study suggests that sexual function may be better in LNG-IUS users, compared with Cu-IUD users, and two studies found an improvement in desire and pain domains of the female sexual function index during LNG-IUS use (Table 1).

Symptoms of the lower urinary tract and pelvic/lower abdominal pain were reported among women treated for HMB by the LNG-IUS or hysterectomy (Table 1). Compared with LNG-IUS use, hysterectomy increased the risks for incomplete emptying, lower urinary tract infections and stress urinary incontinence. Hysterectomy as well as LNG-IUS decreased lower abdominal pain, while only LNG-IUS use could reduce back pain.

Three studies have analyzed the risk of breast cancer in users of the LNG-IUS. One study which compared women diagnosed with breast cancer and with prior or no use of LNG-IUS found that ever-use of LNG-IUS was not associated with increased risk of breast cancer recurrence in women diagnosed with breast cancer.[73] In a sub-analysis, a marginally higher recurrence rate was found among women who developed breast cancer during the use of LNG-IUS and continued its use after the diagnosis compared with women diagnosed with breast cancer who did not use the LNG-IUS.[73] In contrast, in a subanalysis, where patients who started their LNG-IUS use only after completion of primary treatment for breast cancer and were using antiestrogen adjuvant therapy, no increased risk of recurrence of breast cancer was observed compared with women diagnosed with breast cancer and with no use of the LNG-IUS.[73] However, it should be remembered that according to the WHO Medical Eligibility Criteria for Contraceptive Use, the use of LNG-IUS is contraindicated (category 4) for women with current breast cancer. Whereas, its use is category 3 (use of method not usually recommended unless other more appropriate methods are not available or not acceptable) for women with a personal history of breast cancer and no evidence of current disease for 5 years.[102]

Two case–control studies examined the risk of the development of breast cancer during the use of the LNG-IUS. One study found no increase in breast cancer incidence (either tumor induction or promotion) associated with LNG-IUS use when compared with Cu-IUD use in women <50 years of age.[74] This was seen in both crude analyses and after adjusting for known risk factors for breast cancer. This is consistent with an earlier reported cohort study.[77] The second study focused on postmenopausal women using estrogen treatment for climacteric symptoms with cross-linking of cancer registry diagnoses with the national drug reimbursement registry.[75] An increased risk of breast cancer was associated with the LNG-IUS and estrogens, but also LNG-IUS-only use. However, information on several known risk factors for breast cancer was not available in this study and thus could not be adjusted for. Also, the information of exposure was an estimate based on the reimbursement registry without knowledge of actual insertion and removal of the LNG-IUS.[75] Therefore, the results regarding breast cancer risk when the LNG-IUS is used for endometrial protection during estrogen treatment must be interpreted with caution and further studies in postmenopausal women are warranted to confirm or refute the results.

Taken together, current data support that there is no increased risk of primary diagnosis of breast cancer among premenopausal women who use the LNG-IUS, while the risk remains unknown in women using the LNG-IUS together with estrogens for HRT.

Using similar methodology, one study reported on the risk of development of endometrial cancer associated with different types of hormone therapy (HT) regimens, including the LNG-IUS, by postmenopausal women.[76] A decreased risk of endometrial cancer development in users of estrogen therapy (ET) + LNG-IUS, as well as LNG-IUS-only users, was found.

The Use of the LNG-IUS in Nulliparous Women

Wider use of LARCs would be an effective strategy to prevent unplanned pregnancies, and with improved contraceptive counseling, the uptake of LARCs can be increased.[78] Due to its efficacy and additional health benefits, the use of the LNG-IUS among young nulliparous women is expanding rapidly, although there is considerable variation between countries (Table 2).[15,79–86] In the USA, the recommended patient profile for the LNG-IUS includes 'women who have had at least one child' – however, such general restrictions regarding use in nulliparous women are not in place in the countries where the LNG-IUS is marketed the most. Adolescents and nulliparous women are not more likely to prematurely discontinue use of their IUS than adult or parous women.[86] Recent studies have confirmed that the LNG-IUS can also be used for reduction of dysmenorrhea and HMB by young and nulliparous women (Table 2).

The fact that three out of seven studies on the use of LNG-IUS by nulliparous women focused on the insertion procedure indicates that it may be perceived as challenging in this group of women (Table 2). However, in a majority of women, insertion was regarded as technically easy by the healthcare provider and no perforations were reported. Despite the fact that the insertion was experienced as painful by a large proportion of women, this did not negatively influence satisfaction with the LNG-IUS.[80] Compared with 'older' women or parous women, young or nulliparous women were not more likely to have their IUS removed because of dissatisfaction (Table 2).[86] The most common reason for removing the IUS was wish for pregnancy. Return to fertility and 1-year pregnancy rates after removal of the LNG-IUS did not differ from those seen after session of barrier methods or use of no contraceptives.[87]

Taken together, there is increasing evidence to support that the LNG-IUS is a safe and well accepted, highly effective contraceptive method for young and nulliparous women as well as older women. Additional therapeutic effects include reduced HMB and dysmenorrhea.

Despite the evidence described above, the clinical practice seems to have remained unchanged at least in some settings. A survey among general practitioners from the UK showed that the LNG-IUS was not widely promoted or provided to young nulligravid women. Misconceptions relating to pelvic inflammatory disease and risk of ectopic pregnancy and perceived difficulty of insertion in nulligravidae were frequent.[88] Thus, education of healthcare professionals needs to be improved and local guidelines should be updated to encourage the use of the LNG-IUS in young nulliparous women. Encouragingly, planned postabortal use of the LNG-IUS has also increased among teenagers undergoing an induced abortion.[89]

LNG-IUS in the Treatment of HMB

The LNG-IUS is recognized as the most cost-effective nonsurgical method of treatment for HMB, and it has become the first-line recommendation for the treatment of HMB by several national and international guidelines, including the NICE guideline for HMB in the UK. However, a lot of research is still carried out in this indication, and the summary of the clinical trials published within the 5 last years is presented in Table 3.[90–93] In brief, when compared with oral treatments either with cyclic medroxyprogesterone acetate or combined oral contraceptives,[92] the LNG-IUS was superior in reducing menstrual bleeding and in improving blood hemoglobin levels among women suffering from documented menorrhagia.

In addition, two recent reviews have been published on the use of the LNG-IUS in the treatment of menorragia.[91,94]

Pooled analysis of five randomized studies on the treatment of idiopathic menorrhagia concluded that the LNG-IUS is effective in reducing HMB and in increasing body iron stores as evidenced by increases in blood hemoglobin and ferritin levels.[94] The second, more extensive review including all available literature on the use of the LNG-IUS in women with HMB summarized that the LNG-IUS is superior to other medical treatments and comparable to endometrial resection in reducing HMB.[92] Moreover, the high efficacy of the LNG-IUS is seen over a variety of different countries and healthcare settings. Taken together, these reviews highlight the use of the LNG-IUS as the first-line treatment of HMB.

Use of the LNG-IUS as Part of HT for Climacteric Symptoms

The LNG-IUS is also suitable for endometrial protection during ET for climacteric symptoms. A 5-year-long clinical study in perimenopausal women transitioning from contraception to HT with the LNG-IUS reported on the bleeding pattern.[95] Adding ET was not associated with any increase in bleeding/spotting in LNG-IUS users, thus suggesting that it is a good strategy to transition from contraception to menopause. A systematic review and meta-analysis on the LNG-IUS plus ET concluded that the LNG-IUS was more effective than sequential medroxyprogesterone acetate and comparable with other systemic progestogen regimens for endometrial protection in perimenopausal and postmenopausal women taking ET.[96] Another systematic review came to a similar conclusion, stating that the LNG-IUS was at least as effective as other routes of progestin administration in HT.[97]

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