Safety and Efficacy of the Levonorgestrel-releasing Intrauterine System

Table 1.  Recent articles describing safety-related outcomes in levonorgestrel-releasing intrauterine system users.

Study (year)	Topic	Methodology	Main findings	Ref.
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	[48]
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	[49]
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	[50]
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	[51]
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	[52]
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	[53]
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	[54]
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	[55]
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	[56]
Lidegaard et al. (2012)	Arterial thrombosis	Registry-based epidemiological study on stroke and myocardial infarction in users of various contraceptive methods, compared with nonhormonal method users	LNG-IUS use was not associated with an increased risk of stroke or myocardial infarction, compared with nonhormonal method use	[57]
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	[58]
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	[59]
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	[60]
Kaliterna et al. (2011)		Comparison of IUCD users vs noncontraceptors	Escherichia coli and Ureaplasma urealyticum more often isolated from IUCD users than noncontraceptive method users	[61]
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	[62]
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	[63]
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	[64]
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	[65]
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	[66]
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	[67]
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	[68]
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	[69]
Enzlin et al. (2012)		Cross-sectional study of LNG-IUS and copper IUD users using the short sexual functioning scale	LNG-IUS users had similar psychological and sexual functioning compared with copper IUD users. Overall, the influence of IUCD on sexual functioning was small	[70]
Heliövaara-Peippo et al. (2010)	Urinary tract symptoms, lower abdominal/pelvic pain	RCT of LNG-IUS vs hysterectomy in women with HMB	Compared with hysterectomy, LNG-IUS was associated with less urinary tract symptoms and incontinence	[71]
Heliövaara-Peippo et al. (2009)		RCT of LNG-IUS vs hysterectomy in women with HMB	Lower abdominal pain score decreased in both groups, but back pain score decreased only with LNG-IUS	[72]
Trinh et al. (2008)	Breast cancer	Retrospective controlled cohort analysis on recurrence rate in women diagnosed with breast cancer	Overall, no increased risk of breast cancer recurrence associated with the LNG-IUS	[73]
Dinger et al. (2011)		Retrospective, population-based case–control study in women <50 years comparing breast cancer risk in LNG-IUS and copper IUD users	LNG-IUS was associated with no increased risk of breast cancer compared with copper IUD use	[74]
Lyytinen et al. (2010)		Retrospective registry-based case–control study in postmenopausal women using various types of HT	Increased risk of breast cancer risk among the LNG-IUS + estrogen and the LNG-IUS-only users	[75]
Jaakkola et al. (2011)	Endometrial cancer	Retrospective registry-based case–control study in postmenopausal women using various types of HT	Decreased risk of endometrial cancer risk among the LNG-IUS + estrogen and the LNG-IUS-only users	[76]

BMD: Bone mineral density; BV: Bacterial vaginosis; CRP: C-reactive protein; CVD: Cardiovascular disease; FSFI: Female sexual function index; GnRH: Gonadotropin-releasing hormone; HMB: Heavy menstrual bleeding; HRQoL: Health-related quality of life; HT: Hormone therapy; IUCD: Intrauterine contraceptive device; LNG-IUS: Levonorgestrel-releasing intrauterine system; OC: Oral contraception; RCT: Randomized controlled trial; VTE: Venous thromboembolism.

Table 2.  Recently published studies on the use of the levonorgestrel-releasing intrauterine system in young, nulliparous women.

Study (year)	Topic	Methodology	Main findings	Ref.
Bahamondes et al. (2011)	Insertion	Retrospective case–control study nulligravida (n = 159) vs parous women (n = 477)	Insertions judged as easy by >80% of providers, with total failures of <1% and expulsions of 4%	[79]
Marions et al. (2011)	Insertion	Noninterventional study, nulliparous women (n = 224), 12–16 weeks of follow-up	Insertions judged as easy by 72% of providers; 2.6% failed insertions; pain judged as none (9%), moderate (72%) or severe 17%. No perforations or pregnancies. At 12–16 weeks, at 1-year follow-up, 76% satisfied	[80]
Brockmeyer et al. (2008)	Insertion	Prospective pilot study (n = 117), 12-month follow-up	Both IUS and copper IUD well tolerated, high satisfaction and compliance rates	[81]
Aslam et al. (2010)	Dysmenorrhea and HMB	Consecutive case series of 48 adolescents with HMB and dysmenorrhea resistant to oral treatment	93% improvement	[82]
Pillai et al. (2010)		Retrospective study, adolescent with menstrual problems and various medical disorders	LNG-IUS significant therapeutic benefit for 12 out of 14 patients aged 11–21 years	[83]
Paterson et al. (2009)	HMB and contraception	Cohort n = 179 (73% nulliparous)	Most common indications for use are HMB, contraception or both, followed by endometriosis and dysmenorrhea. 1-year continuation rate; 85% cumulative expulsion incidence 8%	[84]
Godfrey et al. (2010)	Compliance	Randomized, pilot study in adolescents (n = 23) LNG-IUS vs copper IUD	Continuation rates at 6 months, LNG-IUS 75% vs copper IUD 45% users	[85]
Behringer et al. (2011)	Compliance	Retrospective cohort study (n = 828), 104 (12.6%) nulliparous women, of which 131 (15.8%) were ≤20 years of age	Nulliparous women did not have more expulsions or removals because of dissatisfaction; this was not different to parous women (6.7 vs 11.5%; p = 0.15)	[86]

HMB: Heavy menstrual bleeding; IUS: Intrauterine system; LNG-IUS: Levonorgestrel-releasing intrauterine system.

COC: Combined oral contraceptive; Hb: Hemoglobin; LNG-IUS: Levonorgestrel-releasing intrauterine system; MBL: Menstrual blood loss; MPA: Medroxyprogesterone acetate; OC: Oral contraceptive; PBAC: Pictorial blood loss assessment chart; RCT: Randomized controlled trial.

Authors and Disclosures

Kristina Gemzell-Danielsson*¹, Pirjo Inki² and Oskari Heikinheimo<sup>3

1</sup>Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet/Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden
²Bayer HealthCare Pharmaceuticals AG, Berlin, Germany
³Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

Financial & competing interests disclosure
P Inki is employed by Bayer HealthCare Pharmaceuticals AG, manufacturer of the LNG-IUS. K Gemzell-Danielsson and O Heikinheimo serve occasionally on advisory boards or act as ad hoc invited speakers at scientific meetings for Bayer HealthCare Pharmaceuticals AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

*Author for correspondence
Tel.: +46 851 772 128 Fax: +46 851 774 314 kristina.gemzell@ki.se

Sidebar

Key Issues

• Use of the levonorgestrel-releasing intrauterine system (LNG-IUS) is increasing worldwide in several indications and in all age groups of women.

• The LNG-IUS is the most cost-effective nonsurgical treatment of heavy menstrual bleeding, it provides similar clinical outcomes compared with endometrial ablation and is a less invasive alternative to hysterectomy and allows fertility preservation.

• Postabortal insertion of the intrauterine contraceptive device (IUCD) has been shown to be an effective means to avoid repeat terminations. Insertion of IUCD should be performed as early as possible following abortion.

• In women with various pre-existing medical conditions (e.g., HIV infection, coagulopathies, obesity), the LNG-IUS does not appear to have adverse effects on the course of the underlying disease.

• The adverse effects of the LNG-IUS are established. Use of the LNG-IUS is not associated with an increased risk of arterial or venous thrombosis, nor with the risk of breast cancer in women of reproductive age. Uterine perforation is a rare complication which should be taken into account, in particular in breast-feeding women.

• The LNG-IUS for endometrial protection as part of hormone therapy for climacteric symptoms is at least as effective as other routes of progestin administration.

• Despite existing evidence on safety, in some settings, healthcare providers still have reservations about using IUCD for nulliparous women. Thus, providers would need to be educated and local guidelines updated according to the available recent information.

• In the future, long-acting reversible contraceptives are expected to become the contraceptive methods of first choice to women throughout their reproductive period owing to their superior effectiveness in real-life use, cost–effectiveness and established safety profile.