Use of Anxiolytic, Hypnotic and Antidepressant Drugs After Dispensation of a Levonorgestrel 52 mg Intra-uterine System Compared to a 19.5 mg Intra-uterine System: A Nationwide Matched-cohort Study

Background: Even administered locally, Levonorgestrel Intra-Uterine Systems (LNG IUSs) might have systemic adverse events such as mood disturbances: several European studies have shown associations between the use of LNG IUS and depression, and anxiolytics drug use. All these studies focused on the utilization of the IUS containing 52 mg of LNG, although a LNG 19.5 mg IUS has been marketed in France since 2018. We hypothesized that the dose of LNG could influence outcomes of mood changes as the low-doses devices correspond to lower serum LNG levels.

Objectives: To determine if there is an increased risk of anxiolytics, hypnotics and antidepressants use among women with a LNG 52 mg IUS comparing with women using a 19.5 mg IUS.

Methods: We conducted a nationwide matched-cohort study using data from the French National Health Insurance database (SNDS), which provides detailed information on health insurance claims for 99% of the population living in France. We identified women aged 13-40 years old who got a 52 mg LNG IUS in 2019 (without previous utilization of a LNG IUS) and a control group who got a 19.5 mg LNG-IUS, matched (1:1) on age (±3 years), pregnancies in the 10 years before, month of delivery in 2019 (±3) and type of physician (general practitioner, gynaecologist or midwife). Conditional logistic regression was used to calculate adjusted odds ratios (aOR) and 95% confidence intervals to study the associations between the type of LNG-IUSs and the use of anxiolytics, hypnotics and antidepressants within two years after dispensing.

Results: A total of 45,736 women with a LNG 52 mg IUS (mean age: 32.3 [5.4]) and 45,736 women with a LNG 19.5 mg IUS (mean age: 31.8 [5.4]) were matched. After adjustment for sociodemographic characteristics, arterial, venous, oncologic and gynaecological history, obesity, use of smoking cessation drugs and the matching variables, having a 52 mg LNG IUS dispensation rather than a 19.5 mg one is associated with the use of antidepressant within the two years after dispensation (aOR=1.13 [1.05-1.22], p< 0.001) but not significantly with the use of anxiolytics (aOR=1.05 [0.99-1.12], p=0.12) and hypnotics (aOR=1.09 [0.99-1.19], p=0.07). Similar results were observed within one year after dispensation. When analysing a subgroup of women with no medical history, having a 52 mg LNG-IUS dispensation rather than a 19.5 mg one is still associated with a significant but low risk of antidepressant use in the two years after dispensation (aOR= 1.19 [1.09-1.31], p< 0.01).

Conclusions: This nationwide study could not exclude a slight increased risk of antidepressant use with the LNG 52 mg IUS when compared with a lower dose of progestin. Further studies are needed to confirm that women would benefit from the low-dose LNG-IUSs.