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Rubik’s cube of depression, antidepressants, and fertility

      Women experience mood and anxiety disorders at an increased prevalence during their reproductive years. As a result, antidepressants are one of the most used prescription medication classes in the United States, used by approximately 15% of reproductive-age women between 15 and 44 years (
      • Dawson A.L.
      • Ailes E.C.
      • Gilboa S.M.
      • Simeone R.M.
      • Lind J.N.
      • Farr S.L.
      • et al.
      Antidepressant prescription claims among reproductive-aged women with private employer-sponsored insurance—United States 2008–2013.
      ). In women who are actively trying to conceive, approximately 10% report antidepressant use (
      • Casilla-Lennon M.M.
      • Meltzer-Brody S.
      • Steiner A.Z.
      The effect of antidepressants on fertility.
      ). The pervasiveness of depressive disorders and subsequent antidepressant use among reproductive-age women has brought attention to concerns regarding the potential effect of these drugs on fertility.
      Prior research on associations between depression, pharmacologic treatment of depression, and the ability to conceive in a given menstrual cycle (fecundability) has yielded mixed results. Conclusions from cross-sectional and retrospective studies are limited by the possibility of reverse causation. Women with more difficulty conceiving may be at higher risk for developing depression and consequently would be more likely to initiate antidepressant use. Unfortunately, efforts to clarify the direction of causality using prospective cohort studies have not yet added clarity.
      Two large, prospective cohort studies evaluating the relationship between depression, self-reported antidepressant use, and fecundability in women actively trying to conceive have produced conflicting results. Whereas one reported a link between antidepressant use and decreased fecundability that persisted after adjusting for history of depression (
      • Casilla-Lennon M.M.
      • Meltzer-Brody S.
      • Steiner A.Z.
      The effect of antidepressants on fertility.
      ), the other found no association between fecundability and antidepressant use independent of depressive symptoms (
      • YI Nillni
      • Wesselink A.K.
      • Gradus J.L.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • et al.
      Depression, anxiety, and psychotropic medication use and fecundability.
      ). In the latter, women with moderate to severe depression had an approximately 30% reduction in fecundability compared with those who had no or mild symptoms, suggesting depression itself and not the antidepressant treatment was responsible for the observed reduction in fecundability.
      In this month’s issue of Fertility and Sterility, Sjaarda et al. (
      • Sjaarda L.A.
      • Radoc J.G.
      • Flannagan K.S.
      • Mumford S.L.
      • Kim K.
      • Perkins N.J.
      • et al.
      Urinary selective serotonin reuptake inhibitors (SSRI) across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss.
      ) aim to delineate the relationship between antidepressant use and fertility by analyzing data and stored urine specimens from participants trying to conceive as part of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial (
      • Schisterman E.F.
      • Silver R.M.
      • Lesher L.L.
      • Faraggi D.
      • Wactawski-Wende J.
      • Townsend J.M.
      • et al.
      Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.
      ). The EAGeR trial was a multicenter prospective trial that included 1,228 women between the ages of 18 and 40 years who had regular menstrual cycles, a history of one to two prior pregnancy losses, and no prior infertility diagnoses. The enrolled participants were monitored for up to six menstrual cycles as they tried to conceive naturally.
      Sjaarda et al. (
      • Sjaarda L.A.
      • Radoc J.G.
      • Flannagan K.S.
      • Mumford S.L.
      • Kim K.
      • Perkins N.J.
      • et al.
      Urinary selective serotonin reuptake inhibitors (SSRI) across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss.
      ) suggest that the mixed findings noted in the prior literature could be due to inaccurate classification of the predictor (self-reported antidepressant use) and/or imprecise measurement of the outcome (home urine pregnancy tests or arrival of menstruation). To circumvent these limitations, the researchers creatively used stored urine specimens to more quantitatively define both the predictor of antidepressant use (analyzing urine from clinic visits for selective serotonin reuptake inhibitor [SSRI] metabolites) and the outcome of pregnancy (analyzing urine from the last 10 days of at-home collection for human chorionic gonadotropin [hCG]). By evaluating urine from the last 10 days of at-home collection before menses, the researchers anticipated the identification of additional early biochemical pregnancies that would have been missed by less precise urine pregnancy tests used at the time of study activities.
      Antidepressant usage was detected in 14% of participants, with the majority testing positive for SSRIs (94%). The authors determined that women with SSRI exposure had a 24% reduction in fecundability (odds ratio 0.72; 95% confidence interval, 0.60–0.96). Meanwhile, the relative risk of pregnancy loss based on SSRI exposure at preconception, cycle of conception, and 4 and 8 weeks of gestation did not differ at any time point between the women with and without SSRI exposure. More reassuringly, the researchers found that women with and without preconception exposure to any SSRI had no statistically significant differences in live-birth outcomes. The subgroup analysis of fluoxetine use, however, did indicate an almost 30% reduction in relative risk of live birth compared with no SSRI use, a trend not observed with the other SSRIs evaluated in this study. Overall, these data suggest an association between preconception SSRI exposure and reduced fecundability, without a subsequent effect on the risk of pregnancy loss or live-birth outcome after successful conception.
      Altogether, the lack of impact on live birth among women using SSRIs is reassuring for the many reproductive-age women managing their depression symptoms with these medications. The strengths of the study include its large and rich data set, with rigorous determination of medication exposures. Some caveats, however, are important to consider when interpreting these findings. First, direct measurement of depression symptoms did not occur. This was simulated in a sensitivity analysis, but some confounding might still be present. Second, only women with one to two prior pregnancy losses were included in the trial, potentially limiting the generalization of the findings. Finally, in the fecundability analysis exposure was characterized on the basis of SSRI metabolites in the urine either at preconception or last visit before conception/sixth failed cycle; this may result in bias because a participant who initiated SSRI use before their sixth failed cycle would be categorized as exposed with an outcome of failure to conceive, which discounts their prior unexposed cycles with failed pregnancies and possibly biasing the analysis.
      It is important to acknowledge that there are well-established clinical risks to untreated depression, and this analysis did not address the possibly serious implications of abrupt cessation of antidepressant medications in women actively trying to conceive. A holistic approach to maternal-fetal health must be taken, with balanced consideration of the maternal risk of depression relapse based on prior history and potential fetal risks associated with use of specific SSRIs.
      Overall, Sjaarda et al. (
      • Sjaarda L.A.
      • Radoc J.G.
      • Flannagan K.S.
      • Mumford S.L.
      • Kim K.
      • Perkins N.J.
      • et al.
      Urinary selective serotonin reuptake inhibitors (SSRI) across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss.
      ) have certainly contributed to the growing literature on antidepressant use and fertility, adding information regarding not only fecundability outcomes but also those of pregnancy loss and live birth. The study’s conclusions resonate with prior literature in its highlight of concerns regarding antidepressant use and decreased fecundability. As the average age of women trying to conceive continues to increase, and as the prevalence of depression and antidepressant use increases with age, the need to further parse out the effect of depression and/or antidepressant use on fecundability will only become more pressing. Future investigations into this complex association would benefit from prospective analysis of the relationship between current severity of depression, variation in antidepressant usage, and resultant fertility outcomes.

      References

        • Dawson A.L.
        • Ailes E.C.
        • Gilboa S.M.
        • Simeone R.M.
        • Lind J.N.
        • Farr S.L.
        • et al.
        Antidepressant prescription claims among reproductive-aged women with private employer-sponsored insurance—United States 2008–2013.
        MMWR Morb Mortal Wkly Rep. 2016; 65: 41-46
        • Casilla-Lennon M.M.
        • Meltzer-Brody S.
        • Steiner A.Z.
        The effect of antidepressants on fertility.
        Am J Obstet Gynecol. 2016; 215: 314.e1-314.e5
        • YI Nillni
        • Wesselink A.K.
        • Gradus J.L.
        • Hatch E.E.
        • Rothman K.J.
        • Mikkelsen E.M.
        • et al.
        Depression, anxiety, and psychotropic medication use and fecundability.
        Am J Obstet Gynecol. 2016; 215: 453.e1-453.e8
        • Sjaarda L.A.
        • Radoc J.G.
        • Flannagan K.S.
        • Mumford S.L.
        • Kim K.
        • Perkins N.J.
        • et al.
        Urinary selective serotonin reuptake inhibitors (SSRI) across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss.
        Fertil Steril. 2020; 114: 1276-1285
        • Schisterman E.F.
        • Silver R.M.
        • Lesher L.L.
        • Faraggi D.
        • Wactawski-Wende J.
        • Townsend J.M.
        • et al.
        Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.
        Lancet. 2014; 384: 29-36

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