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The influence of health care utilization on the association between hormonal contraception initiation and subsequent depression diagnosis and antidepressant use
Journal Pre-proofs Original Research Article The Influence of Health Care Utilization on the Association between Hormonal Contraception Initiation and Subsequent Depression Diagnosis and Antidepressant Use Sarah Ditch, Timothy A. Roberts, Shana Hansen PII: DOI: Reference:
S0010-7824(19)30502-5 https://doi.org/10.1016/j.contraception.2019.12.011 CON 9374
To appear in:
Contraception
Received Date: Revised Date: Accepted Date:
25 July 2019 6 December 2019 11 December 2019
Please cite this article as: S. Ditch, T.A. Roberts, S. Hansen, The Influence of Health Care Utilization on the Association between Hormonal Contraception Initiation and Subsequent Depression Diagnosis and Antidepressant Use, Contraception (2019), doi: https://doi.org/10.1016/j.contraception.2019.12.011
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Title: The Influence of Health Care Utilization on the Association between Hormonal Contraception Initiation and Subsequent Depression Diagnosis and Antidepressant Use
Authors: Ditch, Sarah1; Roberts, Timothy A.2; Hansen, Shana3 1. Adolescent Medicine, San Antonio Uniformed Services Health Education Consortium, 3551 Roger Brooke Dr., Fort Sam Houston, TX, 78234 United States. [email protected] 2. Adolescent Medicine/Pediatrics, Children’s Mercy Kansas City, University of Missouri, Kansas City, School of Medicine, Kansas City, MO, United States. [email protected] 3. Adolescent Medicine/Pediatrics, San Antonio Military Medical Center, 3100 Schofield Rd. Bldg. 1179, Fort Sam Houston, TX, 78234 United States. [email protected]
Corresponding Author: Sarah Ditch, [email protected]
Word Counts: Abstract = 203; Manuscript = 2483
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Abstract
Objective: Assess the influence of healthcare utilization on previously reported associations between contraception initiation, diagnosis of depression, and dispensing of antidepressant medications.
Study Design: Retrospective cohort analysis of insurance records from 272,693 women ages 1234 years old enrolled in the United States Military Healthcare System in September 2014 and followed for 12 months. We compared outcomes of women who initiated hormonal contraception with all women eligible for care and then with women who accessed care during the study month using Kaplan-Meier and Cox proportional hazards analyses.
Results: Women age 12-34 who initiated hormonal contraception experienced a higher risk of depression diagnosis and antidepressant use when compared to all enrolled women but not when compared to women who accessed care. Among those who accessed care, some progestins (i.e., levonorgestrel, Hazard Ratio (HR)=1.46, and norelgestromin, HR=1.93) were associated with an increased rate of depression diagnosis but not antidepressant use; Norethindrone (HR=0.21) was associated with a decreased rate of depression diagnosis.
Conclusion: When compared to women utilizing their health insurance, associations between initiating hormonal contraception and depression diagnosis and antidepressant use decreased
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or disappeared. This suggests that healthcare utilization may have confounded previous reports of an association between hormonal contraception use and depression and antidepressant use.
Keywords: Contraception, Depression, Antidepressant, United States Military
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Implications: Population-based studies have shown an association between starting hormonal contraception and subsequent depression diagnoses. In this study, adjusting for healthcare utilization eliminated this association for most hormonal contraceptive types. This suggests that providers can safely prescribe these medications without significantly increasing the risk of depression diagnoses or antidepressant use.
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1. Introduction
The lifetime prevalence of depression in women is between 17% and 30%, with a peak in the reproductive years [1-2]. Many researchers have examined the association between depression and female reproductive hormones, particularly exogenous hormones. In 1971, depression was declared a known side effect of oral hormonal contraceptives [3] and changes in mood are listed as a possible adverse effect of most hormonal contraceptives on the market today [4]. Prospective research studies have been heterogeneous, demonstrating decreased risk [5-7], no association [8-11], and increased risk [12-13] between hormonal contraceptive use and mood symptoms. Population-based studies, on the other hand, have demonstrated a consistent relationship of hormonal contraceptive use with depression and antidepressant use [14-15]. Anderl et al. recently analyzed National Health and Nutrition Examination Survey (NHANES) data and found that oral hormonal contraception use during adolescence increased a woman’s risk for depression in her lifetime compared to women who never used oral hormonal contraceptives or initiated them for the first time in adulthood [16].
It is important to clarify the relationship between hormonal contraception and mood problems because in developed countries such as the United States, Sweden, and Australia, 60-80% of sexually active women are using some form of hormonal contraception [1, 3, 17]. Identification of an association between depressed mood and hormonal contraception use in general or with exposure to specific progestin types could have important public health implications for prevention of mood disorders among reproductive age women.
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This study investigated the association between initiation of hormonal contraception with depression and antidepressant prescription among reproductive age women enrolled in the United States Military Healthcare System. We hypothesized that there would be a positive relationship between hormonal contraception use and subsequent depression and antidepressant use, but that healthcare utilization was a potential confounder in this relationship.
2. Materials and Methods
We used pre-existing de-identified data from the Military Health System Management Analysis and Reporting Tool (M2) to conduct a retrospective cohort study examining the association of hormonal contraception initiation with a new depression diagnosis or antidepressant prescription. M2 contains medical and pharmacy billing records of all TRICARE Prime beneficiaries for both military and civilian healthcare utilization as well as enrollment status for each month. TRICARE Prime includes all active duty service members, military retirees less than 65 years old, medically retired service members, and members of the National Guard and Reserve who have been activated or have chosen to pay for TRICARE Prime. Spouses and unmarried dependent children less than 26 years old of covered individuals are also eligible.
2.1 Participants
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The sample population in this study was females aged 12-34 enrolled in TRICARE Prime in September 2014 and the prior 12 months. This age range was chosen to be comparable to the results of Skovlund et al [15]. We excluded women who were pregnant, on hormonal contraception, previously diagnosed with a psychiatric disorder (Supplemental Table 1), or prescribed an antidepressant in the prior 12 months from our analysis.
We recorded age group (12-19, 20-24, 25-29, 30-34), eligibility status (active duty service member, active duty family member, retiree, retiree family member), and sponsor's rank (from most junior to most senior: Junior Enlisted (E-1 to E-4), Senior Enlisted (E-5 to E-9), Warrant Officer, Service Academy Cadet, Junior Officer (O-1 to O-3), and Senior Officer (O-4 to O-10)) for each of the women in our sample. A service member’s rank determines income and other benefits [18]. More senior rank is associated with higher level of sponsor education, more years of service, and higher military pay and was used as a proxy for socioeconomic status.
2.2 Design The exposed cohort consisted of women who started a new hormonal contraceptive in the study month and the control cohort was those who did not. These cohorts were observed for 12 months for development of a primary outcome, which included a new diagnosis of depression or an antidepressant prescription.
We assessed hormonal contraceptive use using pharmacy and clinical encounter billing codes. M2 contains a record of all medication dispensing events and amount prescribed. We identified
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prescriptions for contraceptive pills, patches and rings using the American Hospital Formulary Service (AHFS) therapeutic classification code for contraception (681200) and subdivided the prescriptions by contraceptive method and progestin type using National Drug Codes (NDC) numbers. Current Procedural Terminology (CPT) codes were used to identify women initiating (58300 for intrauterine device (IUD) or 11981 for subdermal implant) or terminating (58301 for IUD or 11982 for subdermal implant) use of a long-acting reversible contraceptive. If an IUD was inserted, Healthcare Common Procedure Coding System (HCPCS) and NDC numbers were used to identify the type of intrauterine device used (J7300 and 51285-0204-01 for copper IUD, J7301/J7301/S4981 and 50419-0421-01/50419-0422-01 for levonorgestrel releasing IUD). Copper IUD users were placed in the no hormonal contraception group for all analyses. We excluded women using intrauterine systems of unknown type from all analyses. We identified depressive disorder diagnoses using the following International Classification of Diseases (ICD)9 codes: Major Depression Disorder (296.2x), Prolonged depressive reaction (309.1), Atypical Depressive Disorder (296.82), Depressive disorder unspecified (311), Dysthymic Disorder (300.4), Adjustment Disorder with Depressed Mood (309), and Adjustment Disorder with Mixed Anxiety and Depression (309.28). This list was made using the sorted diagnosis categories in the DSM-IV (Supplemental Table 2) [19]. We identified antidepressant medication prescriptions using the AHFS code for antidepressants (281604) and then further subcategorized the medications prescribed using NDC numbers. We included antidepressant prescriptions regardless of their coded indication with a few exceptions. We did not include tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs) typically prescribed for smoking cessation (Zyban®) or insomnia (Trazodone) (Supplemental Table 3). We identified
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pregnancies using the MS-DRG codes for admissions for childbirth (765-768, 774-775). We assumed that pregnancies began 9 months prior to the admission for childbirth.
2.3 Statistics We compared the rates of our primary outcomes (depression diagnosis or antidepressant prescription) between women who initiated hormonal contraception in September 2014 and those who did not using Kaplan-Meier analysis with a 95% confidence interval. We used the Breslow test to perform pair-wise comparisons of the survival distributions between our control groups and each of the contraceptive variables. We used Cox proportional hazards regression, adjusting age group, eligibility status, and sponsor's rank, to evaluate the independent relationship between outcome measures and progesterone type used. We excluded ethynodiol diacetate from our analysis of the effect of progestin type secondary to the low number of women using this in our sample (16 women). Subjects were followed for up to 12 months until a primary outcome occurred, a subject became pregnant, an exposed subject discontinued hormonal contraceptive, a control subject started hormonal contraception, or the subject was no longer enrolled in TRICARE Prime. Discontinuation was determined by a refill not being dispensed by the pharmacy and therefore not billed for.
We performed our analysis using two different control groups. In our first analysis, we included all eligible women who did not start hormonal contraception in September 2014. The analysis was then performed again using only enrollees that accessed inpatient, outpatient, or pharmacy services during the study month. The exposed group was the same, but the control
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group more accurately represented women utilizing their health insurance. The purpose of this refined control group was to decrease potential bias that a woman eligible for care through one health insurance agency will reliably seek care. This assumption can especially introduce bias when the outcome is a mental health diagnosis.
We conducted all analyses using SPSS software (version 22; IBM Corporation, Armonk, NY). One of the investigators, Dr. Timothy Roberts, is an approved M2 user and was responsible for obtaining study data. The Institutional Review Board of Brooke Army Medical Center, Fort Sam Houston, Texas, and the US Defense Health Agency approved this study.
3. Results
Our study sample included 272,693 women. Most women in this study were family members of Active Duty service members. During September 2014, 3,525 (1.3%) of these women started hormonal contraception and an additional 94,721 (34.7%) women accessed care but did not start hormonal contraception (Figure 1). The demographic differences between the exposed group and the two control groups are shown in Table 1. Combined hormonal contraceptives were the most commonly selected contraceptive method (87.1%). Of these, pills were the most common combined hormonal contraceptive (76.7%), followed by vaginal ring (6.9%), and then hormonal patch (3.5%). Norgestimate was the most common (27.6%) progestin type used, followed by levonorgestrel (16.4%) and norethindrone acetate (12.7%) (Table 2).
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For women who enrolled in TRICARE Prime but did not start hormonal contraception (Enrolled Control Group), 6.3% were diagnosed with depression and 4.7% initiated an antidepressant in the 12-month study period. When we restricted our analyses to women who accessed care during September 2014 (Accessed Care Control Group), these percentages increased to 9.0% and 6.8% respectively (Table 3). Figure 2 shows the estimated 12-month risk of being diagnosed with depression or prescribed an antidepressant for both control groups.
When compared with the Enrolled Control Group, initiation of any of the hormonal contraceptive types, except medroxyprogesterone acetate depot, was associated with a higher risk of depression diagnosis. Initiation of IUD or contraceptive pills, patches or rings was associated with a higher risk of antidepressant use as well (Table 4, Supplemental Figure 1). However, compared to the Accessed Care Control Group, there was no longer an association between hormonal contraceptive type and our outcomes in bivariable analyses (Table 4) or in multivariable analyses adjusting for demographic factors (Table 5).
When compared with the Enrolled Control Group, initiation of contraception containing norgestimate, levonorgestrel, etonogestrel, or norelgestromin was associated with higher frequencies of depression. Use of norgestimate, levonorgestrel, etonogestrel, or norgestrel was associated with a higher frequencies of antidepressant use (Table 3). However, using the Accessed Care Control Group, only use of levonorgestrel and norelgestromin containing contraception was associated with a higher frequencies of depression diagnoses while norethindrone use was associated with a lower frequency (Table 3). These associations
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persisted after adjusting for demographic factors. When compared to the Accessed Care Control Group, there was no association between progestin type started and antidepressant use (Table 5).
In multivariable analyses, women with a history of military service (active duty and medicalretirees) and women with lower socioeconomic status (Junior Enlisted Sponsor) were more likely to be diagnosed with depression and prescribed an antidepressant. Women ages 12-19 years old were the most likely to be diagnosed with depression during our study but the least likely to be prescribed an antidepressant (Table 5).
4. Discussion
Consistent with our initial hypothesis, we found an association between hormonal contraception use and depression diagnosis or antidepressant prescription when looking at insurance records for all eligible women. Restricting our control group to women who accessed care increased the incidence of depression in our control group (9%) and decreased the magnitude of the association of hormonal contraception use with our outcomes. The incidence of depression in our control group after this adjustment also more closely matches previous estimates of the rate among reproductive-age women in the US of 8-16% [20]. This suggests a confounding role of healthcare utilization in the relationship between hormonal contraception use and depression identified in previous studies and illustrates the importance of adjusting for propensity to access care when measuring study outcomes like mental health diagnoses.
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Our study is consistent with other studies suggesting an association between levonorgestrel use and mood symptoms [11, 13]. However, the associations we found of other progestin types with depression and antidepressant use differ from the findings of other population-based studies [14, 15]. Given the observational nature of the data contained in this study and previous studies and the variability in effects of progestin types seen between studies, further prospective trials are needed to clarify these relationships prior to applying these findings into clinical practice.
Other significant findings in this study are the associations between demographic variables and outcome measures. Women with a history of military service or junior enlistee sponsors had increased rates of depression and antidepressant use. Younger-aged women were also more likely to be diagnosed with depression but less likely to start an antidepressant. This is consistent with previous studies which have demonstrated higher rates of antidepressant treatment among adults compared to adolescents, but it differs in finding higher rates of depression diagnoses for adolescents [21]. Future studies should focus on improving depression screening and treatment among these groups.
This study builds on previous work by limiting the control group to individuals actively utilizing their health insurance. This potentially eliminates a source of bias in the assumption that if an individual is eligible for care through one type of insurance that they will utilize it and be captured in the outcome measure. This is not always the case as some individuals do not
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regularly see their primary care physician or use other methods to pay for services (self-pay or another insurance). By limiting our control group to those women who demonstrated that they were actively using their military health insurance, we increased the likelihood that we would capture all outcomes.
Limitations of this study include being a retrospective analysis and using insurance records to measure outcomes. We were dependent on provider diagnosis coding for depression. Patients with mood symptoms who did not present for care might be misclassified in our analysis. We would also not capture outcomes in patients who presented for care with mood symptoms that were not documented in their medical record. While we excluded pregnant women, we included parous women in our study. Postpartum women have a different incidence of depression than the general population (10-19%) [22-23]. This confounder was limited by excluding women who had delivered or had a previous mental health diagnoses in the past year. Also, we did not have a measure of medication adherence or reasons for discontinuation. Women who never started a dispensed medication or women who developed mood symptoms and discontinued use of a contraceptive without presenting for care would be misclassified in our study. Future studies in this area should address these limitations.
In conclusion, this study provides reassurance to providers and patients that use of hormonal contraception in general does not appear to produce a large increase in the risk of depression among reproductive-age women, especially when compared to the risks associated with unplanned pregnancy. Carrying an unplanned pregnancy to term may affect a woman’s
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education, carrier, or other life ambitions leading to significant risk factors for depression such as stress, disappointment, and regret [24]. Herd et al demonstrated that later in life, having a history of unplanned pregnancy was just as significant a predictor of depression as education status (high school diploma vs college education) and marital status [25]. While there appears to be some small increased risk associated with exposure to certain progestins, particularly levonorgestrel-containing products, it is unclear if this is clinically significant. Further study is needed to define the magnitude of this increased risk to help patients and providers select the most effective and safe hormonal contraceptive methods.
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References
[1] Keyes KM, Cheslack-Postava K, Westhoff C, Heim CM, Haloossim M, Walsh K, et al. Association of hormonal contraceptive use with reduced levels of depressive symptoms: a national study of sexually active women in the United States. Am J Epidemiol. 2013 Nov 1;178(9):1378-88. [2] Williams L, Jacka F, Pasco J, Henry M, Dodd S, Nicholson G, et al. The prevalence of mood and anxiety disorders in Australian women. Australas Psychiatry. 2010 Jun;18(3):250-5. [3] Herzberg BN, Johnson AL, Brown S. Depressive symptoms and oral contraceptives. Br Med J. 1970 Oct 17;4(5728):142-5. [4] Toffol E, Heikinheimo O, Koponen P, Luoto R, Partonen T. Hormonal contraception and mental health: results of a population-based study. Hum Reprod. 2011 Nov;26(11):3085-93. [5] Young EA, Kornstein SG, Harvey AT, Wisniewski SR, Barkin J, Fava M, et al. Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Psychoneuroendocrinology. 2007 Aug;32(7):843-53. [6] Studd J, Panay N. Hormones and depression in women. Climacteric. 2004 Dec;7(4):33846. [7] Svendal G, Berk M, Pasco JA, Jacka FN, Lund A, Williams LJ. The use of hormonal contraceptive agents and mood disorders in women. J Affect Disord. 2012 Sep;140(1):92-6.
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[8] Duke JM, Sibbritt DW, Young AF. Is there an association between the use of oral contraception and depressive symptoms in young Australian women?. Contraception. 2007 Jan;75(1):27-31. [9] Robinson SA, Dowell M, Pedulla D, McCauley L. Do the emotional side-effects of hormonal contraceptives come from pharmacologic or psychological mechanisms?. Med Hypotheses. 2004;63(2):268-73. [10] O'Connell K, Davis AR, Kerns J. Oral contraceptives: side effects and depression in adolescent girls. Contraception. 2007 Apr;75(4):299-304. [11] Zethraeus N, Dreber A, Ranehill E, Blomberg L, Labrie F, von Schoultz B, Johannesson M, Hirschberg AL. A first-choice combined oral contraceptive influences general wellbeing in healthy women: a double-blind, randomized, placebo-controlled trial. Fertility and sterility. 2017 May 1;107(5):1238-45. [12] Lundin C, Danielsson KG, Bixo M, Moby L, Bengtsdotter H, Jawad I, et al. Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle-A double-blind, placebo-controlled randomized trial. Psychoneuroendocrinology. 2017 Feb;76:135-143. [13] Shahnazi M, Farshbaf Khalili A, Ranjbar Kochaksaraei F, Asghari Jafarabadi M, Gaza Banoi K, Nahaee J, et al. A comparison of second and third generations combined oral contraceptive pills' effect on mood. Iran Red Crescent Med J. 2014 Aug;16(8):e13628. [14] Lindberg M, Foldemo A, Josefsson A, Wiréhn AB. Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: a
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nationwide population-based study with age-specific analyses. Eur J Contracept Reprod Health Care. 2012 Apr;17(2):106-18. [15] Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Nov 1;73(11):1154-1162. [16] Anderl, C. , Li, G. and Chen, F. S. (2019), Oral contraceptive use in adolescence predicts lasting vulnerability to depression in adulthood. J Child Psychol Psychiatr. [17] Wiréhn AB, Foldemo A, Josefsson A, Lindberg M. Use of hormonal contraceptives in relation to antidepressant therapy: A nationwide population-based study. Eur J Contracept Reprod Health Care. 2010 Feb;15(1):41-7. [18] Pierre-Louis BJ, Moore AD, Hamilton JB. The Military Health Care System May Have the Potential to Prevent Health Care Disparities. J Racial Ethn Health Disparities. 2015 Sep;2(3):280-9. [19] Diagnostic Criteria from DSM-IV-TR. American Psychiatric Association, 2002. [20] Ko JY, Farr SL, Dietz PM, Robbins CL. Depression and treatment among US pregnant and nonpregnant women of reproductive age, 2005-2009. J Womens Health (Larchmt). 2012 Aug;21(8):830-6. [21] Olfson M, Blanco C, Wang S, Laje G, Correll CU. National Trends in the Mental Health Care of Children, Adolescents, and Adults by Office-Based Physicians. JAMA Psychiatry. 2014;71(1):81–90. [22] Roberts TA, Hansen S. Association of Hormonal Contraception with depression in the postpartum period. Contraception. 2017 Dec;96(6):446-452.
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[23] Kiviruusu O, Pietikäinen JT, Kylliäinen A, Pölkki P, Saarenpää-Heikkilä O, Marttunen M, Paunio T, Paavonen EJ. Trajectories of mothers' and fathers' depressive symptoms from pregnancy to 24 months postpartum. J Affect Disord. 2019 Sep 10;260:629-637. [24] Steinberg JR, Rubin LR. Psychological Aspects of Contraception, Unintended Pregnancy, and Abortion. Policy Insights Behav Brain Sci. 2014 Oct;1(1):239-247. [25] Herd P, Higgins J, Sicinski K, Merkurieva I. The Implications of Unintended Pregnancies for Mental Health in Later Life. Am J Public Health. 2016 Mar;106(3):421-9.
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Acknowledgements: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Competing Interests: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government. Primary author, Dr. Sarah Ditch, can be reached at [email protected] for access to study protocol or other additional information.
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Table 1: Sample Demographics Demographics Started hormonal contraception using military healthcare benefit Total Subjects Age Group (years) 12-19 20-24 25-29 30-34 Sponsor Rank Junior Enlisted Senior Enlisted Warrant Officer Service Academy Junior Officer Senior Officer Unknown Eligibility Status Active Duty Family Retiree Family Active Duty Medical Retiree
3525
Enrolled in military insurance program but did not receive contraception and may not have accessed any services (Enrolled Control Group) 269099
Accessed noncontraceptive medical, surgical, or pharmacy care using military insurance benefit (Accessed Control Group) 94721
34.1% 29.0% 20.5% 16.4%
34.9% 20.1% 20.3% 24.7%
27.6% 19.3% 23.6% 29.5%
21.4% 59.3% 2.5% 0.8% 7.4% 8.6%
15.1% 64.6% 2.6% 0.4% 7.2% 10.0% <0.1%
17.9% 62.2% 2.4% 0.7% 8.2% 8.7% <0.1%
53.8% 24.7% 21.5% 0.1%
57.9% 27.1% 14.7% 0.2%
54.9% 21.4% 23.4% 0.4%
Inclusion criteria: Female subjects, ages 12-34 years old, continuously enrolled in the United States military insurance program (TRICARE Prime) in between October 2013 and September 2014. Exclusion criteria: pregnancy, mood disorder diagnoses, antidepressant use, or contraception use in the previous 12 months There were significant differences (p<0.001) in all demographic groups between the women who started contraception and each of the control groups.
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Table 2: Hormonal contraceptives initiated in September 2014 and associated progestin types (n=3525) Contraceptive Type Started Levonogestrel IUS Etonogestrel Implant Depot Medroxyprogesterone Contraceptive Pills, Patches, or Rings Vaginal Ring Patch Pill Progestin Type Norgestimate Levonorgestrel Norethindrone acetate Etonogestrel Drospirenone Norethindrone Medroxyprogesterone Norgestrel Desogestrel Norelgestromin Ethynodiol diacetate
% 3.1% 5.1% 4.7% 87.1% 6.9% 3.5% 76.7% 27.6% 16.4% 12.7% 12.1% 7.7% 6.6% 4.6% 4.4% 3.9% 3.5% 0.4%
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Table 3. Kaplan-Meier estimates of the risk of depression diagnoses and antidepressant initiation in the first 12 months after starting hormonal contraception by progestin type
Progestin Type None (enrolled women) None (only women who accessed healthcare in 9/2014) Norgestimate Levonorgestrel Norethindrone acetate Etonogestrel Drospirenone Norethindrone Depot Medroxyprogesterone Norgestrel Desogestrel Norelgestromin
Depression diagnosis in the first 12 months Mean (95% CI) 6.2% (6.0- 6.4)
Antidepressant use in the first 12 months Mean (95% CI) 4.7% (4.6- 4.8)
9.0% (8.8- 9.2)
6.8% (6.6- 7.0)
9.9% (7.0-12.8)a 12.8% (8.7-16.9)a,b 8.3% (2.8-13.8) 11.2% (7.9-15.5)a 6.0% (2.1- 9.9) 2.5% (0.0- 5.2)b 6.6% (0.0-13.5) 6.7% (1.2-13.2) 6.0% (0.8-11.2) 10.4% (3.7-17.1)a,b
7.1% (4.4- 9.8)a 9.2% (5.5-12.9)a 6.0% (2.1- 9.9) 5.7% (3.0- 8.4)a 4.5% (1.2- 7.8) 3.3% (0.0- 8.0) 1.6% (0.0- 4.7) 8.5% (2.6-14.4)a 3.8% (0.0- 8.5) 8.0% (0.0-17.0)
Estimated 12-month risk of being diagnosed with depression or prescribed antidepressants by progestin type started, among women 12-34 years old who accessed healthcare during September 2014 with no history of mental health diagnoses, antidepressant use, pregnancy, prescription contraceptive use, or lapse in healthcare coverage during the previous 12 months. a: risk significantly different from the risk among all enrolled women not using contraception b: risk significantly different from risk among women who accessed non-contraceptive healthcare in September 2014
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Table 4. Association of contraceptive method initiated in September 2014 with encounters for depression and claims for selective serotonin reuptake inhibitor in the next 12 months
Contraceptive Type Enrolled Control Group Access Control Group Implant Intrauterine Depot medroxyprogesterone Pill, Patch, or Ring
Kaplan-Meier Estimate of Depression Diagnoses Mean (95% CI) 6.2% (6.0- 6.4) 9.0% (8.8- 9.2)
Kaplan-Meier Estimate of SSRI Use Mean (95% CI) 4.6% (4.5- 4.7) 6.8% (6.6- 7.0)
12.9% (7.2-18.6)a 11.7% (4.6-18.8)a
5.3% (2.0- 8.6) 11.1% (4.2-18.0)a
6.6% (0.0-13.5) 8.7% (7.1-10.3)a
1.6% (0.0- 4.7) 5.6% (4.2- 7.0)
a Estimated
rate different from enrolled controlled group. There was no significant difference between the estimated diagnosis and SSRI prescription rate in the access control group when compared to any of the contraceptive types. 95%CI=95% confidence interval Enrolled Control Group: patients who were enrolled in the military health care system but did not access contraception in September 2014 Access Control Group: patients who accessed healthcare in the military healthcare system during September 2014 but did not start contraception Women included in sample had 12 months of continuous enrollment in the military healthcare system and no pregnancies, contraception, antidepressant use, or visits for mental health diagnoses in the previous twelve months.
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Table 5: Adjusted risk of depression diagnoses and antidepressant initiation in the first 12 months after starting hormonal contraception by contraceptive type and progestin type among women who accessed medical care
Dependent Type Active Duty Active Duty Family Retiree Family/Other Medically Retired Age Group 12-19 years old 20-24 years old 25-29 years old 30-34 years old Sponsor's Rank Junior Enlisted Senior Enlisted Warrant Officer Service Academy Junior Officer Senior Officer Contraceptive Type None Implant Intrauterine Injectable Pills, Patch, Ring Progestin Type Access Control Group Norgestimate Levonorgestrel Norethindrone acetate Etonogestrel Drospirenone Norethindrone Medroxyprogesterone Norgestrel Desogestrel Norelgestromin
Risk by Contraceptive Type Risk by Progestin Type Depression Depression Diagnosis SSRI Initiation Diagnosis SSRI Initiation HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 1.00 1.00 1.00 1.00 0.67 (0.63-0.70) 0.91 (0.85-0.97) 0.67 (0.63-0.70) 0.91 (0.85-0.97) 0.53 (0.49-0.58) 0.83 (0.76-0.92) 0.53 (0.49-0.58) 0.84 (0.76-0.92) 0.95 (0.70-1.28) 1.66 (1.25-2.21) 0.95 (0.70-1.28) 1.66 (1.25-2.21) 1.00 0.85 (0.78-0.92) 0.88 (0.82-0.95) 0.93 (0.87-0.99)
1.00 1.00 1.38 (1.25-1.52) 0.85 (0.78-0.92) 1.57 (1.43-1.72) 0.88 (0.82-0.95) 1.75 (1.61-1.91) 0.93 (0.87-1.00)
1.00 1.38 (1.25-1.52) 1.57 (1.44-1.72) 1.75 (1.61-1.91)
1.00 0.73 (0.69-0.78) 0.66 (0.56-0.78) 0.13 (0.08-0.22) 0.46 (0.41-0.51) 0.60 (0.54-0.67)
1.00 0.76 (0.71-0.82) 0.73 (0.61-0.89) 0.20 (0.11-0.37) 0.43 (0.38-0.49) 0.59 (0.52-0.68)
1.00 0.73 (0.69-0.78) 0.66 (0.56-0.78) 0.13 (0.08-0.22) 0.46 (0.41-0.51) 0.60 (0.54-0.67)
1.00 0.76 (0.70-0.82) 0.73 (0.61-0.89) 0.20 (0.11-0.37) 0.43 (0.38-0.49) 0.59 (0.52-0.68)
1.00 1.29 (0.81-2.05) 1.17 (0.72-1.91) 0.52 (0.20-1.39) 1.04 (0.88-1.23)
1.00 0.97 (0.50-1.85) 1.34 (0.79-2.27) 0.21 (0.03-1.51) 1.07 (0.88-1.31) 1.00 1.04 (0.78-1.39) 1.42 (1.05-1.92) 0.98 (0.62-1.53) 1.16 (0.81-1.68) 0.81 (0.45-1.47) 0.21 (0.05-0.85) 0.52 (0.20-1.39) 0.81 (0.36-1.80) 1.09 (0.49-2.43) 1.93 (1.04-3.60)
1.00 1.12 (0.79-1.57) 1.28 (0.87-1.88) 1.03 (0.60-1.77) 1.05 (0.66-1.67) 0.88 (0.44-1.76) 0.46 (0.15-1.42) 0.21 (0.03-1.51) 1.63 (0.81-3.26) 0.79 (0.25-2.44) 1.43 (0.60-3.44)
All models adjust for dependent type, age group, and sponsor’s rank
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S0010-7824(19)30502-5 https://doi.org/10.1016/j.contraception.2019.12.011 CON 9374
To appear in:
Contraception
Received Date: Revised Date: Accepted Date:
25 July 2019 6 December 2019 11 December 2019
Please cite this article as: S. Ditch, T.A. Roberts, S. Hansen, The Influence of Health Care Utilization on the Association between Hormonal Contraception Initiation and Subsequent Depression Diagnosis and Antidepressant Use, Contraception (2019), doi: https://doi.org/10.1016/j.contraception.2019.12.011
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Published by Elsevier Inc.
Title: The Influence of Health Care Utilization on the Association between Hormonal Contraception Initiation and Subsequent Depression Diagnosis and Antidepressant Use
Authors: Ditch, Sarah1; Roberts, Timothy A.2; Hansen, Shana3 1. Adolescent Medicine, San Antonio Uniformed Services Health Education Consortium, 3551 Roger Brooke Dr., Fort Sam Houston, TX, 78234 United States. [email protected] 2. Adolescent Medicine/Pediatrics, Children’s Mercy Kansas City, University of Missouri, Kansas City, School of Medicine, Kansas City, MO, United States. [email protected] 3. Adolescent Medicine/Pediatrics, San Antonio Military Medical Center, 3100 Schofield Rd. Bldg. 1179, Fort Sam Houston, TX, 78234 United States. [email protected]
Corresponding Author: Sarah Ditch, [email protected]
Word Counts: Abstract = 203; Manuscript = 2483
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Abstract
Objective: Assess the influence of healthcare utilization on previously reported associations between contraception initiation, diagnosis of depression, and dispensing of antidepressant medications.
Study Design: Retrospective cohort analysis of insurance records from 272,693 women ages 1234 years old enrolled in the United States Military Healthcare System in September 2014 and followed for 12 months. We compared outcomes of women who initiated hormonal contraception with all women eligible for care and then with women who accessed care during the study month using Kaplan-Meier and Cox proportional hazards analyses.
Results: Women age 12-34 who initiated hormonal contraception experienced a higher risk of depression diagnosis and antidepressant use when compared to all enrolled women but not when compared to women who accessed care. Among those who accessed care, some progestins (i.e., levonorgestrel, Hazard Ratio (HR)=1.46, and norelgestromin, HR=1.93) were associated with an increased rate of depression diagnosis but not antidepressant use; Norethindrone (HR=0.21) was associated with a decreased rate of depression diagnosis.
Conclusion: When compared to women utilizing their health insurance, associations between initiating hormonal contraception and depression diagnosis and antidepressant use decreased
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or disappeared. This suggests that healthcare utilization may have confounded previous reports of an association between hormonal contraception use and depression and antidepressant use.
Keywords: Contraception, Depression, Antidepressant, United States Military
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Implications: Population-based studies have shown an association between starting hormonal contraception and subsequent depression diagnoses. In this study, adjusting for healthcare utilization eliminated this association for most hormonal contraceptive types. This suggests that providers can safely prescribe these medications without significantly increasing the risk of depression diagnoses or antidepressant use.
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1. Introduction
The lifetime prevalence of depression in women is between 17% and 30%, with a peak in the reproductive years [1-2]. Many researchers have examined the association between depression and female reproductive hormones, particularly exogenous hormones. In 1971, depression was declared a known side effect of oral hormonal contraceptives [3] and changes in mood are listed as a possible adverse effect of most hormonal contraceptives on the market today [4]. Prospective research studies have been heterogeneous, demonstrating decreased risk [5-7], no association [8-11], and increased risk [12-13] between hormonal contraceptive use and mood symptoms. Population-based studies, on the other hand, have demonstrated a consistent relationship of hormonal contraceptive use with depression and antidepressant use [14-15]. Anderl et al. recently analyzed National Health and Nutrition Examination Survey (NHANES) data and found that oral hormonal contraception use during adolescence increased a woman’s risk for depression in her lifetime compared to women who never used oral hormonal contraceptives or initiated them for the first time in adulthood [16].
It is important to clarify the relationship between hormonal contraception and mood problems because in developed countries such as the United States, Sweden, and Australia, 60-80% of sexually active women are using some form of hormonal contraception [1, 3, 17]. Identification of an association between depressed mood and hormonal contraception use in general or with exposure to specific progestin types could have important public health implications for prevention of mood disorders among reproductive age women.
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This study investigated the association between initiation of hormonal contraception with depression and antidepressant prescription among reproductive age women enrolled in the United States Military Healthcare System. We hypothesized that there would be a positive relationship between hormonal contraception use and subsequent depression and antidepressant use, but that healthcare utilization was a potential confounder in this relationship.
2. Materials and Methods
We used pre-existing de-identified data from the Military Health System Management Analysis and Reporting Tool (M2) to conduct a retrospective cohort study examining the association of hormonal contraception initiation with a new depression diagnosis or antidepressant prescription. M2 contains medical and pharmacy billing records of all TRICARE Prime beneficiaries for both military and civilian healthcare utilization as well as enrollment status for each month. TRICARE Prime includes all active duty service members, military retirees less than 65 years old, medically retired service members, and members of the National Guard and Reserve who have been activated or have chosen to pay for TRICARE Prime. Spouses and unmarried dependent children less than 26 years old of covered individuals are also eligible.
2.1 Participants
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The sample population in this study was females aged 12-34 enrolled in TRICARE Prime in September 2014 and the prior 12 months. This age range was chosen to be comparable to the results of Skovlund et al [15]. We excluded women who were pregnant, on hormonal contraception, previously diagnosed with a psychiatric disorder (Supplemental Table 1), or prescribed an antidepressant in the prior 12 months from our analysis.
We recorded age group (12-19, 20-24, 25-29, 30-34), eligibility status (active duty service member, active duty family member, retiree, retiree family member), and sponsor's rank (from most junior to most senior: Junior Enlisted (E-1 to E-4), Senior Enlisted (E-5 to E-9), Warrant Officer, Service Academy Cadet, Junior Officer (O-1 to O-3), and Senior Officer (O-4 to O-10)) for each of the women in our sample. A service member’s rank determines income and other benefits [18]. More senior rank is associated with higher level of sponsor education, more years of service, and higher military pay and was used as a proxy for socioeconomic status.
2.2 Design The exposed cohort consisted of women who started a new hormonal contraceptive in the study month and the control cohort was those who did not. These cohorts were observed for 12 months for development of a primary outcome, which included a new diagnosis of depression or an antidepressant prescription.
We assessed hormonal contraceptive use using pharmacy and clinical encounter billing codes. M2 contains a record of all medication dispensing events and amount prescribed. We identified
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prescriptions for contraceptive pills, patches and rings using the American Hospital Formulary Service (AHFS) therapeutic classification code for contraception (681200) and subdivided the prescriptions by contraceptive method and progestin type using National Drug Codes (NDC) numbers. Current Procedural Terminology (CPT) codes were used to identify women initiating (58300 for intrauterine device (IUD) or 11981 for subdermal implant) or terminating (58301 for IUD or 11982 for subdermal implant) use of a long-acting reversible contraceptive. If an IUD was inserted, Healthcare Common Procedure Coding System (HCPCS) and NDC numbers were used to identify the type of intrauterine device used (J7300 and 51285-0204-01 for copper IUD, J7301/J7301/S4981 and 50419-0421-01/50419-0422-01 for levonorgestrel releasing IUD). Copper IUD users were placed in the no hormonal contraception group for all analyses. We excluded women using intrauterine systems of unknown type from all analyses. We identified depressive disorder diagnoses using the following International Classification of Diseases (ICD)9 codes: Major Depression Disorder (296.2x), Prolonged depressive reaction (309.1), Atypical Depressive Disorder (296.82), Depressive disorder unspecified (311), Dysthymic Disorder (300.4), Adjustment Disorder with Depressed Mood (309), and Adjustment Disorder with Mixed Anxiety and Depression (309.28). This list was made using the sorted diagnosis categories in the DSM-IV (Supplemental Table 2) [19]. We identified antidepressant medication prescriptions using the AHFS code for antidepressants (281604) and then further subcategorized the medications prescribed using NDC numbers. We included antidepressant prescriptions regardless of their coded indication with a few exceptions. We did not include tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs) typically prescribed for smoking cessation (Zyban®) or insomnia (Trazodone) (Supplemental Table 3). We identified
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pregnancies using the MS-DRG codes for admissions for childbirth (765-768, 774-775). We assumed that pregnancies began 9 months prior to the admission for childbirth.
2.3 Statistics We compared the rates of our primary outcomes (depression diagnosis or antidepressant prescription) between women who initiated hormonal contraception in September 2014 and those who did not using Kaplan-Meier analysis with a 95% confidence interval. We used the Breslow test to perform pair-wise comparisons of the survival distributions between our control groups and each of the contraceptive variables. We used Cox proportional hazards regression, adjusting age group, eligibility status, and sponsor's rank, to evaluate the independent relationship between outcome measures and progesterone type used. We excluded ethynodiol diacetate from our analysis of the effect of progestin type secondary to the low number of women using this in our sample (16 women). Subjects were followed for up to 12 months until a primary outcome occurred, a subject became pregnant, an exposed subject discontinued hormonal contraceptive, a control subject started hormonal contraception, or the subject was no longer enrolled in TRICARE Prime. Discontinuation was determined by a refill not being dispensed by the pharmacy and therefore not billed for.
We performed our analysis using two different control groups. In our first analysis, we included all eligible women who did not start hormonal contraception in September 2014. The analysis was then performed again using only enrollees that accessed inpatient, outpatient, or pharmacy services during the study month. The exposed group was the same, but the control
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group more accurately represented women utilizing their health insurance. The purpose of this refined control group was to decrease potential bias that a woman eligible for care through one health insurance agency will reliably seek care. This assumption can especially introduce bias when the outcome is a mental health diagnosis.
We conducted all analyses using SPSS software (version 22; IBM Corporation, Armonk, NY). One of the investigators, Dr. Timothy Roberts, is an approved M2 user and was responsible for obtaining study data. The Institutional Review Board of Brooke Army Medical Center, Fort Sam Houston, Texas, and the US Defense Health Agency approved this study.
3. Results
Our study sample included 272,693 women. Most women in this study were family members of Active Duty service members. During September 2014, 3,525 (1.3%) of these women started hormonal contraception and an additional 94,721 (34.7%) women accessed care but did not start hormonal contraception (Figure 1). The demographic differences between the exposed group and the two control groups are shown in Table 1. Combined hormonal contraceptives were the most commonly selected contraceptive method (87.1%). Of these, pills were the most common combined hormonal contraceptive (76.7%), followed by vaginal ring (6.9%), and then hormonal patch (3.5%). Norgestimate was the most common (27.6%) progestin type used, followed by levonorgestrel (16.4%) and norethindrone acetate (12.7%) (Table 2).
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For women who enrolled in TRICARE Prime but did not start hormonal contraception (Enrolled Control Group), 6.3% were diagnosed with depression and 4.7% initiated an antidepressant in the 12-month study period. When we restricted our analyses to women who accessed care during September 2014 (Accessed Care Control Group), these percentages increased to 9.0% and 6.8% respectively (Table 3). Figure 2 shows the estimated 12-month risk of being diagnosed with depression or prescribed an antidepressant for both control groups.
When compared with the Enrolled Control Group, initiation of any of the hormonal contraceptive types, except medroxyprogesterone acetate depot, was associated with a higher risk of depression diagnosis. Initiation of IUD or contraceptive pills, patches or rings was associated with a higher risk of antidepressant use as well (Table 4, Supplemental Figure 1). However, compared to the Accessed Care Control Group, there was no longer an association between hormonal contraceptive type and our outcomes in bivariable analyses (Table 4) or in multivariable analyses adjusting for demographic factors (Table 5).
When compared with the Enrolled Control Group, initiation of contraception containing norgestimate, levonorgestrel, etonogestrel, or norelgestromin was associated with higher frequencies of depression. Use of norgestimate, levonorgestrel, etonogestrel, or norgestrel was associated with a higher frequencies of antidepressant use (Table 3). However, using the Accessed Care Control Group, only use of levonorgestrel and norelgestromin containing contraception was associated with a higher frequencies of depression diagnoses while norethindrone use was associated with a lower frequency (Table 3). These associations
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persisted after adjusting for demographic factors. When compared to the Accessed Care Control Group, there was no association between progestin type started and antidepressant use (Table 5).
In multivariable analyses, women with a history of military service (active duty and medicalretirees) and women with lower socioeconomic status (Junior Enlisted Sponsor) were more likely to be diagnosed with depression and prescribed an antidepressant. Women ages 12-19 years old were the most likely to be diagnosed with depression during our study but the least likely to be prescribed an antidepressant (Table 5).
4. Discussion
Consistent with our initial hypothesis, we found an association between hormonal contraception use and depression diagnosis or antidepressant prescription when looking at insurance records for all eligible women. Restricting our control group to women who accessed care increased the incidence of depression in our control group (9%) and decreased the magnitude of the association of hormonal contraception use with our outcomes. The incidence of depression in our control group after this adjustment also more closely matches previous estimates of the rate among reproductive-age women in the US of 8-16% [20]. This suggests a confounding role of healthcare utilization in the relationship between hormonal contraception use and depression identified in previous studies and illustrates the importance of adjusting for propensity to access care when measuring study outcomes like mental health diagnoses.
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Our study is consistent with other studies suggesting an association between levonorgestrel use and mood symptoms [11, 13]. However, the associations we found of other progestin types with depression and antidepressant use differ from the findings of other population-based studies [14, 15]. Given the observational nature of the data contained in this study and previous studies and the variability in effects of progestin types seen between studies, further prospective trials are needed to clarify these relationships prior to applying these findings into clinical practice.
Other significant findings in this study are the associations between demographic variables and outcome measures. Women with a history of military service or junior enlistee sponsors had increased rates of depression and antidepressant use. Younger-aged women were also more likely to be diagnosed with depression but less likely to start an antidepressant. This is consistent with previous studies which have demonstrated higher rates of antidepressant treatment among adults compared to adolescents, but it differs in finding higher rates of depression diagnoses for adolescents [21]. Future studies should focus on improving depression screening and treatment among these groups.
This study builds on previous work by limiting the control group to individuals actively utilizing their health insurance. This potentially eliminates a source of bias in the assumption that if an individual is eligible for care through one type of insurance that they will utilize it and be captured in the outcome measure. This is not always the case as some individuals do not
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regularly see their primary care physician or use other methods to pay for services (self-pay or another insurance). By limiting our control group to those women who demonstrated that they were actively using their military health insurance, we increased the likelihood that we would capture all outcomes.
Limitations of this study include being a retrospective analysis and using insurance records to measure outcomes. We were dependent on provider diagnosis coding for depression. Patients with mood symptoms who did not present for care might be misclassified in our analysis. We would also not capture outcomes in patients who presented for care with mood symptoms that were not documented in their medical record. While we excluded pregnant women, we included parous women in our study. Postpartum women have a different incidence of depression than the general population (10-19%) [22-23]. This confounder was limited by excluding women who had delivered or had a previous mental health diagnoses in the past year. Also, we did not have a measure of medication adherence or reasons for discontinuation. Women who never started a dispensed medication or women who developed mood symptoms and discontinued use of a contraceptive without presenting for care would be misclassified in our study. Future studies in this area should address these limitations.
In conclusion, this study provides reassurance to providers and patients that use of hormonal contraception in general does not appear to produce a large increase in the risk of depression among reproductive-age women, especially when compared to the risks associated with unplanned pregnancy. Carrying an unplanned pregnancy to term may affect a woman’s
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education, carrier, or other life ambitions leading to significant risk factors for depression such as stress, disappointment, and regret [24]. Herd et al demonstrated that later in life, having a history of unplanned pregnancy was just as significant a predictor of depression as education status (high school diploma vs college education) and marital status [25]. While there appears to be some small increased risk associated with exposure to certain progestins, particularly levonorgestrel-containing products, it is unclear if this is clinically significant. Further study is needed to define the magnitude of this increased risk to help patients and providers select the most effective and safe hormonal contraceptive methods.
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References
[1] Keyes KM, Cheslack-Postava K, Westhoff C, Heim CM, Haloossim M, Walsh K, et al. Association of hormonal contraceptive use with reduced levels of depressive symptoms: a national study of sexually active women in the United States. Am J Epidemiol. 2013 Nov 1;178(9):1378-88. [2] Williams L, Jacka F, Pasco J, Henry M, Dodd S, Nicholson G, et al. The prevalence of mood and anxiety disorders in Australian women. Australas Psychiatry. 2010 Jun;18(3):250-5. [3] Herzberg BN, Johnson AL, Brown S. Depressive symptoms and oral contraceptives. Br Med J. 1970 Oct 17;4(5728):142-5. [4] Toffol E, Heikinheimo O, Koponen P, Luoto R, Partonen T. Hormonal contraception and mental health: results of a population-based study. Hum Reprod. 2011 Nov;26(11):3085-93. [5] Young EA, Kornstein SG, Harvey AT, Wisniewski SR, Barkin J, Fava M, et al. Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Psychoneuroendocrinology. 2007 Aug;32(7):843-53. [6] Studd J, Panay N. Hormones and depression in women. Climacteric. 2004 Dec;7(4):33846. [7] Svendal G, Berk M, Pasco JA, Jacka FN, Lund A, Williams LJ. The use of hormonal contraceptive agents and mood disorders in women. J Affect Disord. 2012 Sep;140(1):92-6.
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[8] Duke JM, Sibbritt DW, Young AF. Is there an association between the use of oral contraception and depressive symptoms in young Australian women?. Contraception. 2007 Jan;75(1):27-31. [9] Robinson SA, Dowell M, Pedulla D, McCauley L. Do the emotional side-effects of hormonal contraceptives come from pharmacologic or psychological mechanisms?. Med Hypotheses. 2004;63(2):268-73. [10] O'Connell K, Davis AR, Kerns J. Oral contraceptives: side effects and depression in adolescent girls. Contraception. 2007 Apr;75(4):299-304. [11] Zethraeus N, Dreber A, Ranehill E, Blomberg L, Labrie F, von Schoultz B, Johannesson M, Hirschberg AL. A first-choice combined oral contraceptive influences general wellbeing in healthy women: a double-blind, randomized, placebo-controlled trial. Fertility and sterility. 2017 May 1;107(5):1238-45. [12] Lundin C, Danielsson KG, Bixo M, Moby L, Bengtsdotter H, Jawad I, et al. Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle-A double-blind, placebo-controlled randomized trial. Psychoneuroendocrinology. 2017 Feb;76:135-143. [13] Shahnazi M, Farshbaf Khalili A, Ranjbar Kochaksaraei F, Asghari Jafarabadi M, Gaza Banoi K, Nahaee J, et al. A comparison of second and third generations combined oral contraceptive pills' effect on mood. Iran Red Crescent Med J. 2014 Aug;16(8):e13628. [14] Lindberg M, Foldemo A, Josefsson A, Wiréhn AB. Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: a
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nationwide population-based study with age-specific analyses. Eur J Contracept Reprod Health Care. 2012 Apr;17(2):106-18. [15] Skovlund CW, Mørch LS, Kessing LV, Lidegaard Ø. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Nov 1;73(11):1154-1162. [16] Anderl, C. , Li, G. and Chen, F. S. (2019), Oral contraceptive use in adolescence predicts lasting vulnerability to depression in adulthood. J Child Psychol Psychiatr. [17] Wiréhn AB, Foldemo A, Josefsson A, Lindberg M. Use of hormonal contraceptives in relation to antidepressant therapy: A nationwide population-based study. Eur J Contracept Reprod Health Care. 2010 Feb;15(1):41-7. [18] Pierre-Louis BJ, Moore AD, Hamilton JB. The Military Health Care System May Have the Potential to Prevent Health Care Disparities. J Racial Ethn Health Disparities. 2015 Sep;2(3):280-9. [19] Diagnostic Criteria from DSM-IV-TR. American Psychiatric Association, 2002. [20] Ko JY, Farr SL, Dietz PM, Robbins CL. Depression and treatment among US pregnant and nonpregnant women of reproductive age, 2005-2009. J Womens Health (Larchmt). 2012 Aug;21(8):830-6. [21] Olfson M, Blanco C, Wang S, Laje G, Correll CU. National Trends in the Mental Health Care of Children, Adolescents, and Adults by Office-Based Physicians. JAMA Psychiatry. 2014;71(1):81–90. [22] Roberts TA, Hansen S. Association of Hormonal Contraception with depression in the postpartum period. Contraception. 2017 Dec;96(6):446-452.
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[23] Kiviruusu O, Pietikäinen JT, Kylliäinen A, Pölkki P, Saarenpää-Heikkilä O, Marttunen M, Paunio T, Paavonen EJ. Trajectories of mothers' and fathers' depressive symptoms from pregnancy to 24 months postpartum. J Affect Disord. 2019 Sep 10;260:629-637. [24] Steinberg JR, Rubin LR. Psychological Aspects of Contraception, Unintended Pregnancy, and Abortion. Policy Insights Behav Brain Sci. 2014 Oct;1(1):239-247. [25] Herd P, Higgins J, Sicinski K, Merkurieva I. The Implications of Unintended Pregnancies for Mental Health in Later Life. Am J Public Health. 2016 Mar;106(3):421-9.
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Acknowledgements: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Competing Interests: The view(s) expressed herein are those of the author(s) and do not reflect the official policy or position of Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of the Air Force, or the Department of Defense or the U.S. Government. Primary author, Dr. Sarah Ditch, can be reached at [email protected] for access to study protocol or other additional information.
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Table 1: Sample Demographics Demographics Started hormonal contraception using military healthcare benefit Total Subjects Age Group (years) 12-19 20-24 25-29 30-34 Sponsor Rank Junior Enlisted Senior Enlisted Warrant Officer Service Academy Junior Officer Senior Officer Unknown Eligibility Status Active Duty Family Retiree Family Active Duty Medical Retiree
3525
Enrolled in military insurance program but did not receive contraception and may not have accessed any services (Enrolled Control Group) 269099
Accessed noncontraceptive medical, surgical, or pharmacy care using military insurance benefit (Accessed Control Group) 94721
34.1% 29.0% 20.5% 16.4%
34.9% 20.1% 20.3% 24.7%
27.6% 19.3% 23.6% 29.5%
21.4% 59.3% 2.5% 0.8% 7.4% 8.6%
15.1% 64.6% 2.6% 0.4% 7.2% 10.0% <0.1%
17.9% 62.2% 2.4% 0.7% 8.2% 8.7% <0.1%
53.8% 24.7% 21.5% 0.1%
57.9% 27.1% 14.7% 0.2%
54.9% 21.4% 23.4% 0.4%
Inclusion criteria: Female subjects, ages 12-34 years old, continuously enrolled in the United States military insurance program (TRICARE Prime) in between October 2013 and September 2014. Exclusion criteria: pregnancy, mood disorder diagnoses, antidepressant use, or contraception use in the previous 12 months There were significant differences (p<0.001) in all demographic groups between the women who started contraception and each of the control groups.
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Table 2: Hormonal contraceptives initiated in September 2014 and associated progestin types (n=3525) Contraceptive Type Started Levonogestrel IUS Etonogestrel Implant Depot Medroxyprogesterone Contraceptive Pills, Patches, or Rings Vaginal Ring Patch Pill Progestin Type Norgestimate Levonorgestrel Norethindrone acetate Etonogestrel Drospirenone Norethindrone Medroxyprogesterone Norgestrel Desogestrel Norelgestromin Ethynodiol diacetate
% 3.1% 5.1% 4.7% 87.1% 6.9% 3.5% 76.7% 27.6% 16.4% 12.7% 12.1% 7.7% 6.6% 4.6% 4.4% 3.9% 3.5% 0.4%
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Table 3. Kaplan-Meier estimates of the risk of depression diagnoses and antidepressant initiation in the first 12 months after starting hormonal contraception by progestin type
Progestin Type None (enrolled women) None (only women who accessed healthcare in 9/2014) Norgestimate Levonorgestrel Norethindrone acetate Etonogestrel Drospirenone Norethindrone Depot Medroxyprogesterone Norgestrel Desogestrel Norelgestromin
Depression diagnosis in the first 12 months Mean (95% CI) 6.2% (6.0- 6.4)
Antidepressant use in the first 12 months Mean (95% CI) 4.7% (4.6- 4.8)
9.0% (8.8- 9.2)
6.8% (6.6- 7.0)
9.9% (7.0-12.8)a 12.8% (8.7-16.9)a,b 8.3% (2.8-13.8) 11.2% (7.9-15.5)a 6.0% (2.1- 9.9) 2.5% (0.0- 5.2)b 6.6% (0.0-13.5) 6.7% (1.2-13.2) 6.0% (0.8-11.2) 10.4% (3.7-17.1)a,b
7.1% (4.4- 9.8)a 9.2% (5.5-12.9)a 6.0% (2.1- 9.9) 5.7% (3.0- 8.4)a 4.5% (1.2- 7.8) 3.3% (0.0- 8.0) 1.6% (0.0- 4.7) 8.5% (2.6-14.4)a 3.8% (0.0- 8.5) 8.0% (0.0-17.0)
Estimated 12-month risk of being diagnosed with depression or prescribed antidepressants by progestin type started, among women 12-34 years old who accessed healthcare during September 2014 with no history of mental health diagnoses, antidepressant use, pregnancy, prescription contraceptive use, or lapse in healthcare coverage during the previous 12 months. a: risk significantly different from the risk among all enrolled women not using contraception b: risk significantly different from risk among women who accessed non-contraceptive healthcare in September 2014
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Table 4. Association of contraceptive method initiated in September 2014 with encounters for depression and claims for selective serotonin reuptake inhibitor in the next 12 months
Contraceptive Type Enrolled Control Group Access Control Group Implant Intrauterine Depot medroxyprogesterone Pill, Patch, or Ring
Kaplan-Meier Estimate of Depression Diagnoses Mean (95% CI) 6.2% (6.0- 6.4) 9.0% (8.8- 9.2)
Kaplan-Meier Estimate of SSRI Use Mean (95% CI) 4.6% (4.5- 4.7) 6.8% (6.6- 7.0)
12.9% (7.2-18.6)a 11.7% (4.6-18.8)a
5.3% (2.0- 8.6) 11.1% (4.2-18.0)a
6.6% (0.0-13.5) 8.7% (7.1-10.3)a
1.6% (0.0- 4.7) 5.6% (4.2- 7.0)
a Estimated
rate different from enrolled controlled group. There was no significant difference between the estimated diagnosis and SSRI prescription rate in the access control group when compared to any of the contraceptive types. 95%CI=95% confidence interval Enrolled Control Group: patients who were enrolled in the military health care system but did not access contraception in September 2014 Access Control Group: patients who accessed healthcare in the military healthcare system during September 2014 but did not start contraception Women included in sample had 12 months of continuous enrollment in the military healthcare system and no pregnancies, contraception, antidepressant use, or visits for mental health diagnoses in the previous twelve months.
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Table 5: Adjusted risk of depression diagnoses and antidepressant initiation in the first 12 months after starting hormonal contraception by contraceptive type and progestin type among women who accessed medical care
Dependent Type Active Duty Active Duty Family Retiree Family/Other Medically Retired Age Group 12-19 years old 20-24 years old 25-29 years old 30-34 years old Sponsor's Rank Junior Enlisted Senior Enlisted Warrant Officer Service Academy Junior Officer Senior Officer Contraceptive Type None Implant Intrauterine Injectable Pills, Patch, Ring Progestin Type Access Control Group Norgestimate Levonorgestrel Norethindrone acetate Etonogestrel Drospirenone Norethindrone Medroxyprogesterone Norgestrel Desogestrel Norelgestromin
Risk by Contraceptive Type Risk by Progestin Type Depression Depression Diagnosis SSRI Initiation Diagnosis SSRI Initiation HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) 1.00 1.00 1.00 1.00 0.67 (0.63-0.70) 0.91 (0.85-0.97) 0.67 (0.63-0.70) 0.91 (0.85-0.97) 0.53 (0.49-0.58) 0.83 (0.76-0.92) 0.53 (0.49-0.58) 0.84 (0.76-0.92) 0.95 (0.70-1.28) 1.66 (1.25-2.21) 0.95 (0.70-1.28) 1.66 (1.25-2.21) 1.00 0.85 (0.78-0.92) 0.88 (0.82-0.95) 0.93 (0.87-0.99)
1.00 1.00 1.38 (1.25-1.52) 0.85 (0.78-0.92) 1.57 (1.43-1.72) 0.88 (0.82-0.95) 1.75 (1.61-1.91) 0.93 (0.87-1.00)
1.00 1.38 (1.25-1.52) 1.57 (1.44-1.72) 1.75 (1.61-1.91)
1.00 0.73 (0.69-0.78) 0.66 (0.56-0.78) 0.13 (0.08-0.22) 0.46 (0.41-0.51) 0.60 (0.54-0.67)
1.00 0.76 (0.71-0.82) 0.73 (0.61-0.89) 0.20 (0.11-0.37) 0.43 (0.38-0.49) 0.59 (0.52-0.68)
1.00 0.73 (0.69-0.78) 0.66 (0.56-0.78) 0.13 (0.08-0.22) 0.46 (0.41-0.51) 0.60 (0.54-0.67)
1.00 0.76 (0.70-0.82) 0.73 (0.61-0.89) 0.20 (0.11-0.37) 0.43 (0.38-0.49) 0.59 (0.52-0.68)
1.00 1.29 (0.81-2.05) 1.17 (0.72-1.91) 0.52 (0.20-1.39) 1.04 (0.88-1.23)
1.00 0.97 (0.50-1.85) 1.34 (0.79-2.27) 0.21 (0.03-1.51) 1.07 (0.88-1.31) 1.00 1.04 (0.78-1.39) 1.42 (1.05-1.92) 0.98 (0.62-1.53) 1.16 (0.81-1.68) 0.81 (0.45-1.47) 0.21 (0.05-0.85) 0.52 (0.20-1.39) 0.81 (0.36-1.80) 1.09 (0.49-2.43) 1.93 (1.04-3.60)
1.00 1.12 (0.79-1.57) 1.28 (0.87-1.88) 1.03 (0.60-1.77) 1.05 (0.66-1.67) 0.88 (0.44-1.76) 0.46 (0.15-1.42) 0.21 (0.03-1.51) 1.63 (0.81-3.26) 0.79 (0.25-2.44) 1.43 (0.60-3.44)
All models adjust for dependent type, age group, and sponsor’s rank
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