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. 2025 Mar 3;8(3):e252474.
doi: 10.1001/jamanetworkopen.2025.2474.

Postpartum Hormonal Contraceptive Use and Risk of Depression

Søren Vinther Larsen  1   2 , Brice Ozenne  1   3 , Anders Pretzmann Mikkelsen  4   5 , Xiaoqin Liu  6 , Kathrine Bang Madsen  6 , Trine Munk-Olsen  7 , Øjvind Lidegaard  2   4 , Vibe Gedsø Frokjaer  1   2   8
Affiliations

Postpartum Hormonal Contraceptive Use and Risk of Depression

Søren Vinther Larsen et al. JAMA Netw Open. .

Abstract

Importance: Hormonal contraceptive (HC) use is associated with depression. It is, however, unknown whether this is also true in the postpartum period when women have a heightened depression risk and are routinely offered HC treatment.

Objective: To examine whether HC initiation post partum is associated with the development of depression within 12 months post partum.

Design, setting, and participants: A population-based cohort study based on nationwide Danish register data was conducted including all primiparous women who gave birth from January 1, 1997, through December 31, 2022. Women were excluded if they had depression within 24 months before delivery, multiple births or stillbirth, or a diagnosis of breast cancer or liver tumor. Data analysis was conducted between March 20, 2023, and January 17, 2025.

Exposure: Hormonal contraceptive initiation within 12 months post partum was treated as a time-varying exposure. Hormonal contraceptive types were categorized as combined oral contraceptives (COCs), combined nonoral contraceptives (CNOCs), progestogen-only pills (POPs), and progestogen-only nonoral contraceptives (PNOCs).

Main outcomes and measures: Depression within 12 months post partum, defined as filling an antidepressant prescription or receiving a hospital diagnosis of depression, was the main outcome. Adjusted hazard ratios (AHRs) and average absolute risks of depression within 12 months post partum were estimated using Cox proportional hazards regression and a G-formula estimator.

Results: Of 610 038 first-time mothers, 248 274 (40.7%) initiated HCs within 12 months post partum (mean [SD] age, 27.6 [4.3] years for HC users vs 29.6 [4.8] years for nonusers). Hormonal contraceptive initiation was associated with subsequent depression, with an AHR of 1.49 (95% CI, 1.42-1.56) compared with no use, resulting in an increase in the 12-month absolute risk from 1.36% (95% CI, 1.32%-1.39%) to 1.54% (95% CI, 1.50%-1.57%). The AHR for COC was 1.72 (95% CI, 1.63-1.82); CNOC, 1.97 (95% CI, 1.64-2.36); and PNOC, 1.40 (95% CI, 1.25-1.56). Progestogen-only pill exposure was associated with an instantaneously reduced risk in the early study period, but it was increased late post partum. The earlier COCs were initiated post partum the higher the associated rate ratio of depression.

Conclusions and relevance: In this cohort study, HC initiation post partum was associated with an instantaneous increased risk of developing depression. The associated risk was higher the earlier it was initiated post partum, at least for COC. This finding raises the issue of whether the incidence of depression post partum is increased by routine HC initiation after childbirth.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bang Madsen reported receiving personal fees from Medice Nordic within the past 3 years. Dr Munk-Olsen reported receiving speaker’s fees from Lundbeck A/S outside the submitted work. Dr Lidegaard reported receiving an institutional grant from Exeltis to Juliane Marie Center for a postmarketing thrombosis study on a progestogen-only pill during the conduct of the study; the author did not receive any personal payment for his work. Dr Frokjaer reported receiving lecture fees from Lundbeck Pharma A/S, Janssen-Cilag A/S, Gedeon-Richter A/S, and Ferring A/S outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Risks of Depression at 12 Months Post Partum
A, Average absolute risk of depression within 12 months from delivery under scenario 0 (observed initiation of hormonal contraceptive [HC] post partum) vs scenario 1 (nobody had initiated HC). B, Average absolute risk difference within 12 months post partum between these 2 scenarios. C, Average absolute risk of depression within 12 months from delivery for the scenarios where all mothers who were observed to initiate HC initiated only combined oral contraceptive (COC) (scenario 2), combined nonoral contraceptive (CNOC) (scenario 3), progestogen-only pill (POP) (scenario 4), or progestogen-only nonoral contraceptive (PNOC) (scenario 5), with the observed transition intensity observed for each type vs if nobody had initiated HC. D, Average absolute risk difference within 12 months post partum contrasting scenario 0 to scenarios 2 to 5. Shaded areas indicate 95% CIs.
Figure 2.
Figure 2.. Postpartum Timing of Combined Oral Contraceptive Initiation and Depression Rate Ratio Compared With Nonexposed Mothers
Ratio between an exposed mother who starts a t-year (x-axis) and a nonexposed mother in a model with a spline on the time to initiation without including time since initiation as a time scale. When assuming a linear relationship instead of a spline, the association between depression rate ratio in exposed vs nonexposed mothers and time to initiation was estimated to 0.61 (95% CI, 0.48-0.79). This means that the rate ratio decreases with time to initiation, but as illustrated by the graph, the rate ratio remains above 1 for first-time mothers who initiated treatment across all 12 months post partum compared with the nonexposed; however, after 7 months, it was estimated with high uncertainty due to the short remaining follow-up time.
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References

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