By Rebecca H. Allen, MD, MPH
Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck, and has served as a consultant for Bayer and Pharmanest.
SYNOPSIS: In this three-month randomized, double-blind trial comparing oral contraceptives to placebo, the authors found a small decrease in general well-being scores but no effect on depressive symptoms. The short time period and small effect size introduce doubt into the validity of these findings.
SOURCE: Zethraeus N, Dreber A, Ranehill E, et al. A first choice combined oral contraceptive influences general well-being in healthy women: A double-blind, randomized, placebo-controlled trial. Fertil Steril 2017; Apr 10. doi: 10.1016/j.fertnstert.2017.02.120. [Epub ahead of print].
This randomized, double-blind, placebo-controlled trial was conducted over a three-month time period in Stockholm, Sweden. The investigators randomized women who were between 18-35 years of age and who had a body mass index (BMI) between 19-30 kg/m2 and regular menstrual cycles not using any hormonal contraceptive to a monophasic oral contraceptive (OC) pill containing 150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol or placebo. Exclusion criteria were any contraindication to combined oral contraceptives or any intake of sex steroid hormones during the six weeks prior to beginning the study. At the baseline visit on day 1 to day 7 of the menstrual cycle, participants completed the Psychological General Well-Being Index (PGWBI) and the Beck Depression Inventory (BDI) and a general physical exam was performed. The PGWBI measures general well-being in the past month with 22 questions and six domains. The score ranges from 0 (poor quality of life) to 110 (good quality of life), with a score ≤ 72 indicating moderate to severe distress in general well-being. The BDI measures depressive symptoms and attitudes during the previous week with
21 questions, and scores range from 0 to 63, with ≥ 20 indicating moderate to severe depressive symptoms. The primary outcome measure after three cycles was the global score on the PGWBI, and secondary outcomes were scores on each PGWBI dimension: anxiety, depressed mood, positive well-being, self-control, general health, and vitality. The primary outcome of depressive symptoms was the BDI global score.
The investigators enrolled 340 women between February 2012 and August 2015 (169 in the OC group and 171 in the placebo group). Ultimately, 332 women had data for analysis. There was no difference between the groups at baseline in terms of age, education, marital status, BMI, proportion with moderate to severe distress in general well-being on the PGWBI (35.1% placebo vs. 34.9% OC), or proportion with moderate to severe depressive symptoms on the BDI (7% placebo vs. 7.1% OC). After three months of treatment, this changed to 38% in the placebo group and 44% in the OC group with moderate to severe distress in general well-being on the PGWBI and no change in the BDI. When examining the mean change in the global score of PGWBI between the OC and placebo groups, the authors found a change of -4.12 (95% confidence interval [CI], -7.18 to -1.06; P = .0085), which corresponded to a 6% reduction. For the dimensions of the PGWBI, the only other statistically significant decreases were in positive well-being (-3.90; 95% CI, -7.78 to 0.01; P = 0.0492), self-control (-6.63; 95% CI, -11.20 to -2.06; P = 0.0046), and vitality (-6.84; 95% CI, -10.80 to -2.88; P = 0.0008). There were no differences in anxiety, depressed mood, or general health.
COMMENTARY
Adherence to OC pills is notoriously poor, leading to a typical use failure rate of 9% in the first year.1 Continuation rates also are low compared to long-acting reversible contraceptives at one year (85% vs. 55%).2 Certainly, continuation rates and adherence could be influenced by side effects. Previous studies have examined the effect of OCs on mood, and most studies show no significant effect on depression.3 A recent cohort study that demonstrated an association between hormonal contraception and subsequent use of antidepressants was reviewed in the December 2016 edition of OB/GYN Clinical Alert.4 Dr. Jensen highlighted several limitations of that study, including small effect size and bias.
The authors of this study speculated that adherence issues also could be related to side effects of OCs, leading to a decreased general well-being of the woman. They sought to examine both depressed mood and general well-being in a three-month randomized, controlled trial. The press release accompanying this study was entitled, “Oral contraceptives reduce general well-being in healthy women.”5 This statement is quite alarming and could lead the lay public to assume that OCs are harmful. In fact, OCs are safe and well-tolerated by the majority of women. Given that unintended pregnancy also is associated with adverse outcomes for women,6 we need to be careful how the study’s findings are interpreted and communicated. The actual findings of the study are quite modest and there are significant limitations.
The main criticism of the study, which the authors acknowledge, is the three-month time period. Most oral contraceptive nuisance side effects, such as unscheduled bleeding, will resolve after three months. Therefore, the findings might have differed if the time period were extended longer. In addition, because of unscheduled bleeding, some participants in the OC arm may have guessed their assignment correctly, and this may have influenced their responses. Furthermore, participating in this research study may have altered subjects’ responses if they were not relying on the OC for contraception as they would in real life. All subjects knew that they were randomized and were told to use condoms for additional protection. It just seems to me that when the stakes do not involve balancing unintended pregnancy with OC side effects, women might have different judgments. Finally, the degree of mean change in the PGWBI overall score, 6%, while statistically significant, does not seem clinically important to me. The authors argued that it is, but looking at the proportion of women with a score of ≤ 72 indicating moderate to severe distress, the OC group was 44% at the end of the study and the placebo group was 38%. Again, this is not a large difference, and the findings should be interpreted with caution. Moreover, these results may apply only to this particular formulation of the OC pill.
As clinicians, we all know individual women who may have discontinued combined OCs because of side effects. We work with women to find a contraceptive method that suits them, and this may change over their lifetime. A blanket statement that OCs will reduce their general well-being is not helpful in my opinion. For some women, freedom from the worry of unintended pregnancy actually may improve their quality of life.
REFERENCES
- Trussell J, Guthrie K. Choosing a Contraceptive: Efficacy, Safety, and Personal Considerations. Hatcher RA, Trussell J, Nelson AL, et al., eds. In: Contraceptive Technology, 20th Edition. New York: Ardent Media Inc; 2011.
- Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol 2011;117:1105-1113.
- Pagano HP, Zapata LB, Berry-Bibee EN, et al. Safety of hormonal contraception and intrauterine devices among women with depressive and bipolar disorders: A systematic review. Contraception 2016;94:641-649.
- Skovlund CW, Morch LS, Kessing LV, Lidegaard O. Association of hormonal contraception with depression. JAMA Psychiatry 2016;73:1154-1162.
- Karolinska Institutet. Oral contraceptives reduce general well-being in healthy women. Available at: http://ki.se/en/news/oral-contraceptives-reduce-general-well-being-in-healthy-women. Accessed April 24, 2017.
- ACOG Committee Opinion Number 654. Reproductive Life Planning to Reduce Unintended Pregnancy. February 2016.
In this three-month randomized, double-blind trial comparing oral contraceptives to placebo, the authors found a small decrease in general well-being scores but no effect on depressive symptoms. The short time period and small effect size introduce doubt into the validity of these findings.
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