The approval of the primary hormonal contraceptive (HC) in 1960 was a historic turning level for ladies, providing unprecedented autonomy over reproductive decisions and higher management over the trajectories of their lives. As such, entry to contraception is now recognised as a world human proper (World Well being Organisation, 2014).
An estimated 40% of reproductive-aged ladies use hormonal contraceptive (HCs) (Kristensen, 2021), however discontinuation is widespread as a result of perceived psychological uncomfortable side effects (Martell, 2023). Regardless of this, epidemiological analysis assessing the hyperlink between HCs and temper adjustments or despair has yielded combined outcomes. Some research report a protecting affect of HCs on temper in particular populations, e.g., these with premenopausal dysphoric dysfunction (PMDD) (Robakis, 2019), whereas different research have reported a destructive affiliation or null findings for HCs and depressive signs (Skovlund, 2016; Worly, 2018). These inconsistencies could also be defined by between-study variation; extra analysis is required to know this relationship, accounting for nuances concerning the affect of various exogenous hormone formulations and deliveries (e.g., long-acting versus oral strategies), and in numerous populations.
This weblog entry opinions findings from a latest Danish examine (Larsen et al, 2024) which estimated the threat of despair in new customers of three totally different doses of the levonorgestrel-releasing intrauterine system (LNG-IUS). This work is important not solely to offer knowledgeable counselling to customers but additionally to assist equitable entry to contraception by addressing obstacles associated to concern concerning uncomfortable side effects.
The influences of hormonal contraceptives on psychological well being have been a longstanding concern for ladies of reproductive age. This new potential cohort examine examines despair threat in new customers of the levonorgestrel-releasing intrauterine system (LNG-IUS).
Strategies
This was a potential examine utilizing knowledge from the Danish nationwide well being registry. The examine pattern included ladies residing in Denmark who:
- Have been born in 1978 or later,
- Began utilizing an LNG-IUS between the ages of 15 and 44, and
- Had no earlier psychological well being dysfunction.
Incident despair was decided utilizing diagnostic information or prescription of antidepressants inside 12 months of LNG-IUS insertion. Danger of despair was calculated utilizing Cox regression, adjusted for different recognized and measured confounders (i.e., age, training, household historical past of psychological well being dysfunction, postpartum IUS use and medical issues for which a high-dose IUS is indicated).
Outcomes
The evaluation included 149,200 new customers of the LNG-IUS; 14.8%, 32% and 53.3% of whom used a low, medium and excessive dose system, respectively. Excessive-dose IUS customers have been extra prone to be older, to have had youngsters, and to have been recognized with a medical indication for an LNG-IUS (e.g., heavy menstrual bleeding, dysmenorrhoea, endometriosis or uterine fibroids).
The entire variety of despair circumstances, primarily based on each diagnoses and antidepressant prescriptions, was 2,258. After 12 months, the proportion of low, medium and excessive dose LNG-IUS customers with despair was 1.21%, 1.46%, and 1.84%, respectively. This interprets to 0.26% extra of the medium dose group having despair in comparison with the low dose group, and 0.63% extra within the excessive in comparison with low dose group; comparatively modest variations in threat.
Instances of despair have been predominantly recognized via antidepressant prescriptions (n=2,110), whereas 366 ladies had obtained a proper prognosis. To beat potential bias from together with ladies who obtained antidepressants for situations aside from despair (e.g., anxiousness issues, power ache situations, premenstrual dysphoric dysfunction [PMDD]), the evaluation was rerun with these for which despair was specified because the indication (n=1,198). On this case, absolutely the dangers have been 0.59% (low dose), 0.70% (medium dose), and 1.02% (excessive dose).
The danger variations between low–medium and low–excessive doses have been small; nevertheless, a dose–response sample (i.e., more and more larger threat with the next levonorgestrel dose) was evident whatever the technique used to determine despair circumstances.
The elevated threat of despair within the high- in comparison with the low-dose LNG-IUS group persevered following a sequence of robustness checks. For instance, the authors carried out separate analyses with the next parameters: nulliparous ladies (i.e., with no start historical past); ladies below the age of 30; and people who initiated an LNG-IUS after 2017 (to beat bias from variable prescription patterns over time). Utilizing propensity rating weighting, an evaluation method that goals to imitate randomisation of baseline traits inside the examine pattern, the authors once more discovered a dose–response relationship between levonorgestrel dose and despair threat.
One other evaluation utilizing solely these with a previous psychological well being dysfunction prognosis (48,937 ladies) reported dangers for low, medium and excessive dose LNG-IUS to be 4.80%, 5.22% and 5.91%, respectively. On this evaluation, the distinction within the proportion of excessive in comparison with low dose LNG-IUS customers who developed despair (1.11%) is bigger than within the group with no prior psychological well being prognosis, suggesting that this group could also be barely extra delicate to the elevated LNG dose.
Twelve months following insertion of an LNG-IUS, the next dose of levonorgestrel was related to a barely larger threat of despair; nevertheless, the danger was low general.
Conclusions
The authors concluded that their examine:
gives proof of a dose-dependent affiliation between LNG publicity and threat of subsequent despair throughout three dosages, which was constant after contemplating potential confounders, akin to menstrual bleeding indications for high-dose LNG-IUS use.
A spread of further robustness checks have been carried out to beat sources of bias, and this dose-dependent relationship persevered whatever the evaluation parameters. Nevertheless, it should be acknowledged that the danger variations (0.27 to 0.66%) have been modest between low and medium to excessive LNG doses, respectively, and that this small elevated threat of despair should be thought-about alongside different potential useful results. Clinicians must be aware that larger LNG-IUS doses could marginally enhance the danger of despair, however the alternative of LNG dose ought to finally be holistically knowledgeable, accounting for comorbid situations and affected person preferences.
Increased levonorgestrel dose was linked to the next threat of despair in a dose–dependent method. Nevertheless, the general threat distinction between high and low dose LNG-IUS was modest.
Strengths and limitations
Nordic nations are famend for his or her glorious contributions to epidemiological analysis as a result of their population-based registries that present routinely collected, just about full potential knowledge (Laugesen et al. 2021). This Danish examine is an instance of such, benefitting from a big pattern measurement spanning the extent of the nationwide inhabitants, and consequently, has a excessive degree of statistical energy main to express estimates and a vastly lowered likelihood of choice bias. Moreover, such registries have a excessive optimistic predictive worth for despair (people flagged as having despair usually tend to be precisely recognized—there are fewer “false positives”).
The examine additionally did nicely to handle confounding by gynaecological situations that are sometimes handled with high-dose LNG-IUS, postpartum initiation, and historical past of psychological well being issues. Potential sources of bias have been addressed via conducting a sequence of sensitivity analyses, every of which maintained a dose-dependent sample for despair threat by growing levonorgestrel dose.
Nevertheless, some limitations should be famous. As steered by Soares (2024) in an editorial response, the exclusion of non-LNG-IUS customers signifies that absolutely the dangers of despair should not given in context of the final inhabitants. The annual incidence charge of despair in Danish ladies is roughly 1.3% (Musliner et al. 2019); due to this fact, low to medium dose LNG-IUS customers could not incur a meaningfully larger threat than could be anticipated normally. This is a vital consideration when decoding outcomes.
It’s attainable that this examine underestimated the true threat of incident despair, as despair diagnoses have been taken from the Psychiatric Central Register however have been unavailable for major care. There could also be a subset of sufferers with milder depressive signs who could have obtained counselling centered on way of life adjustments moderately than medical intervention. Moreover, delicate unfavourable reactions to earlier hormonal contraceptives have been unknown; it’s attainable that ladies have been switched to LNG-IUS who’ve an current sensitivity to exogenous hormones.
Lastly, whereas variations between the three dosing teams have been adjusted for in analyses, there stays an opportunity that different unknown or unmeasured components could have influenced outcomes.
This examine benefitted from a nationally consultant pattern measurement, and thus, excessive statistical energy and exact estimates. Limitations included the potential for unmeasured confounding and the dearth of information on milder depressive signs.
Implications for apply
Contraceptive counselling is just not all the time simple. Medical professionals should weigh up the dangers and advantages of a variety of hormonal or non-hormonal choices, all whereas contemplating the distinctive wants of every particular person by way of their medical historical past, way of life, earlier contraceptive experiences, and their private preferences. The complicated relationship between hormonal contraceptives and psychological well being is just not nicely understood, with combined findings for protecting results, elevated dangers or null findings for various contraceptives and despair.
Larsen et al. (2024) present novel proof for an growing threat of incident despair because the dose of LNG-IUS will increase. Contemplating the dose–response sample and the complementary preclinical proof for the results of levonorgestrel on related mechanistic pathways within the central and peripheral nervous methods, it’s believable that levonorgestrel does modestly enhance despair threat. Nevertheless, given the observational nature of this examine, causal relationships can’t be established.
Additionally it is noteworthy that the absolute despair threat was solely marginally larger than that anticipated within the normal inhabitants. For prime-dose LNG-IUS, roughly one in each 152 ladies could develop medical despair inside 12 months following initiation, in comparison with low dose or the final inhabitants. This may very well be thought-about a small threat general.
On the identical time, it will be significant for healthcare suppliers to concentrate on this small threat. It has been thought that the LNG-IUS acts solely inside the intrauterine atmosphere and that it has little affect on widespread physiological processes, for instance, inside the central nervous system. The dose–dependent sample recognized on this analysis means that exogenous hormones from the LNG-IUS could certainly affect despair threat, maybe defined by affect of neuroendocrine pathways, akin to potentiation of hypothalamic-pituitary-adrenal (HPA) axis reactivity (Aleknaviciute et al. 2017). Healthcare suppliers ought to validate affected person’s considerations concerning anticipated results of the LNG-IUS on psychological well being outcomes and think about monitoring for signs, particularly in these with a psychiatric historical past or prior sensitivity to different hormonal contraceptives.
Moreover, this examine captured despair diagnoses or antidepressant prescriptions, which doubtless represents ladies with extra extreme depressive signs; but it’s attainable that ladies could expertise milder signs that nonetheless have an effect on their high quality of life. Subsequently, the comparatively small threat of despair estimated by this examine shouldn’t be used to dismiss sufferers’ considerations. Future analysis is warranted to discover LNG-IUS influences on a wider vary of psychological well being signs and at totally different severities.
The next levonorgestrel dose is related to a barely elevated threat of despair; nevertheless, this small threat ought to all the time be weighed up towards different potential advantages of a better LNG-IUS dose (e.g., treating different well being situations).
Assertion of pursuits
I at the moment supervise a DPhil pupil who’s learning the affect of postpartum LNG-IUS on breastfeeding charges.
Hyperlinks
Main paper
Larsen SV, Mikkelsen AP, Ozenne B, et al. Affiliation Between Intrauterine System Hormone Dosage and Melancholy Danger. American Journal of Psychiatry 2024; 181(9) 834–841. https://psychiatryonline.org/doi/full/10.1176/appi.ajp.20230909.
Different references
World Well being Organisation (WHO). Guaranteeing human rights within the provision of contraceptive data and providers: Steering and proposals. 2014. Geneva Switzerland Division of Reproductive Well being and Analysis.
https://iris.who.int/bitstream/deal with/10665/102539/9789241506748_eng.pdf;sequence=1
Kristensen SI, Lidegaard Ø. Hormonal contraceptive use in Denmark 2010-2019. Dan Med J. 2021; 68(6).
https://content material.ugeskriftet.dk/websites/default/recordsdata/scientific_article_files/2021-05/a08200599_web.pdf
Martell S, Marini C, Kondas CA et al. Psychological uncomfortable side effects of hormonal contraception: a disconnect between sufferers and suppliers. Contracept Reprod Med. 2023; 8(9). https://doi.org/10.1186/s40834-022-00204-w
Robakis T, Williams KE, Nutkiewicz L. et al. Hormonal Contraceptives and Temper: Overview of the Literature and Implications for Future Analysis. Curr Psychiatry Rep 2019;21(57). https://doi.org/10.1007/s11920-019-1034-z
Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Affiliation of Hormonal Contraception with Melancholy. JAMA Psychiatry. 2016;73(11):1154–1162. doi:10.1001/jamapsychiatry.2016.2387
Worly BL, Gur TL, Schaffir J. The connection between progestin hormonal contraception and despair: a scientific overview. Contraception. 2018;97(6):478–489.
https://www.sciencedirect.com/science/article/pii/S0010782418300325?casa_token=wS982ncxPCUAAAAA:y-UQcrwyQHRkj81OYeLNcHr-B8581rp58G5XERqbb1kWrxwB9_1_MorHaUAxt0As_N7kO4byprA#ab0005
Laugesen Ok, Ludvigsson JF, Schmidt M, et al. Nordic Well being Registry-Primarily based Analysis: A Overview of Well being Care Techniques and Key Registries. Clin Epidemiol. 2021;13:533–554. https://pmc.ncbi.nlm.nih.gov/articles/PMC8302231/#:~:textual content=Thepercent20Nordicpercent20registriespercent20providepercent20population,uppercent20andpercent20exactpercent20censoringpercent20information.
Soares CN. Contraception, Intrauterine Techniques, and Melancholy: Can We Spot the Actual Perpetrator? Am J of Psych. 2024; 181(9):789–92. https://psychiatryonline.org/doi/full/10.1176/appi.ajp.20240647.
Musliner KL, Liu X, Gasse C, et al. Incidence of medically handled despair in Denmark amongst people 15–44 years outdated: a complete overview primarily based on inhabitants registers. Acta Psychiatr Scand. 2019; 139:548–557. https://pubmed.ncbi.nlm.nih.gov/30908590/
Aleknaviciute J, Tulen JHM, De Rijke YB, et al; The levonorgestrel-releasing intrauterine system potentiates stress reactivity. Psychoneuroendocrinology 2017; 80:39–45.
https://europepmc.org/article/med/28315609
