Commentary Nonspecific side effects of oral contraceptives: nocebo or noise? David A. Grimes ⁎ , Kenneth F. Schulz Family Health International, Research Triangle Park, NC 27709, USA Department of Obstetrics and Gynecology, UNC School of Medicine, Chapel Hill, NC 27599-7570, USA Received 16 June 2010; accepted 21 June 2010 Abstract Side effects of combined oral contraceptives are the most common reason why women discontinue them. Over the past half century, an elaborate mythology about these ill effects has evolved, fueled by rumor, gossip and poor-quality research. In contrast, placebo-controlled randomized trials document that nonspecific side effects are not significantly more common with combined oral contraceptives than with inert pills. These reported nonspecific side effects may reflect the nocebo phenomenon (the inverse of a placebo): if women are told to expect noxious side effects, these complaints occur because of the power of suggestion. Alternatively, nonspecific complaints may simply reflect their background prevalence in the population. Because Level I evidence documents no important increase in nonspecific side effects with oral contraceptives, counseling about these side effects or including them in package labeling is unwarranted and probably unethical. When in doubt, clinicians should err on the side of optimism. © 2011 Elsevier Inc. All rights reserved. Keywords: Oral contraceptive; Nonspecific; Side effect; Adverse event; Nocebo “…an incredible amount of effort, investigational time, money, and printed paper have been wasted on oral contra- ceptive trials which uniformly failed to include the necessary controls” [1]. 1. Introduction Nonspecific side effects are the most common reason why women quit taking oral contraceptives. Indeed, studies around the world consistently identify reported side effects as the principal reason for pill discontinuation [2]. In the 2002 National Survey of Family Growth, the 12-month discontinuation rate for oral contraceptives (corrected for underreporting of abortion) was 33% (95% CI 30–35%) [3]. That a third of US pill users stop this contraceptive method within a year has profound adverse public health implica- tions [4-6]. Most of these women switch to a less effective contraceptive or, worse yet, to no method at all [7]. In addition, women who are unhappy with oral contraceptives because of alleged side effects are prone to inconsistent use, which can lead to irregular bleeding and then to discontin- uation because of the bleeding [8]. Women around the world share a common mythology about alleged ill effects of oral contraceptives [9]. A recent systematic review of the international literature (including 28 studies) on attitudes about oral contraceptives revealed widespread concern about perceived side effects [10]. Even if respondents could not name any side effect, many women still associated pills with health problems. This mythology, which dates back decades [11], is perpetuated by gossip, rumors and illogic. The misinformation transcends con- tinents [12-14] and is shared by highly educated women as well as by women with little education [15]. Most studies that have described nonspecific pill side effects did not have appropriate comparison groups [16]. Thus, no conclusions could be drawn about whether these nonspecific side effects were caused by oral contraceptives. For example, FDA-approved package labeling for oral contraceptives contains lengthy lists of side effects that have been reported in pill users. However, without a control group, one cannot infer that these side effects were due to the pills. A common error in logic is post hoc ergo propter hoc reasoning: “after this, therefore because of this.” In this commentary, we will summarize the Level I evidence concerning vague pill side effects, describe the Contraception 83 (2011) 5 – 9 ⁎ Corresponding author. Tel.: +1 919 544 7040; fax: +1 919 544 7261. E-mail address: dgrimes@fhi.org (D.A. Grimes). 0010-7824/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2010.06.010