Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant.

Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception.

Primary outcome: live birth. Secondary outcomes: pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS).

Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score ≥10 was used to define currently active MD.

To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments.

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Depression, as defined by the presence of moderate or severe depressive symptoms, affects 7.4% of Americans aged 18–39 years and is more common among women (9.3%) than men (5.8%) (). Studies have shown that depression is even more common in women with infertility (), with one study reporting a 41% prevalence of depression in women seeking fertility treatments (). Furthermore, it has been reported that women with depression are less likely to conceive and have a lower live birth rate after in vitro fertilization (IVF) treatment (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.75–0.98; and OR 0.83, 95% CI 0.72–0.96; respectively) (). Studies in couples undergoing non-IVF treatments are limited and are necessary to more adequately counsel patients, because a majority of patients with infertility elect to undergo non-IVF procedures. The effects of depression outcomes can not be directly extrapolated from the IVF literature as many techniques used in IVF could potentially overcome many of the proposed mechanisms regarding the effect of depression on fertility, including sexual function, libido, and sperm quality.

Similar to their female counterparts, men seeking fertility treatments also have an increased prevalence of depression (), with one study reporting a 49.1% prevalence of depression in men undergoing IVF treatments (). Although most studies investigating depression, fertility, and pregnancy outcomes focus on the female partner, there is a developing body of literature regarding the effect of depression on semen parameters. Studies have demonstrated a decrease in sperm concentration (); however, data indicating whether or not this translates to poorer fertility treatment outcomes are lacking. Furthermore, studies accounting for the potential effect of both female and male partner depression as well as female antidepressant use are lacking.

Treatment of depression with the use of antidepressant medication is common. An estimated 9.2% of reproductive-age American women (18–39 year old) are currently using an antidepressant (). Antidepressant use in pregnancy has been associated with an increased risk of pregnancy complications, including miscarriage (), but many of these studies did not account for the effect of the underlying depression, nor did they control for other risk factors or elective terminations. Furthermore, there are limited data on antidepressant use, fertility potential, and fertility treatment outcomes. Although it is generally thought that the benefits obtained from antidepressant use outweigh these risks (), the effects on pregnancy outcome may be based on the type of antidepressant medication used, such as selective serotonin reuptake inhibitors (SSRIs) and non-SSRI medications (). A review by Domar et al. in 2013 revealed that although there were no statistically significant differences in pregnancy rates among infertile women using an SSRI medication in any of the studies under review, there was also no clear evidence of benefit (). A majority of the studies were conducted in couples pursuing IVF, and therefore it is possible that technologies used during IVF treatments could overcome the effect of depression for all subjects and so no difference is noted with the use of antidepressant treatment. It is unclear whether antidepressant use in the absence of these technologies would improve fertility treatment outcomes.

The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond.

Primary care screening for and treatment of depression in pregnant and postpartum women evidence report and systematic review for the US Preventive Services Task Force.

Many infertile couples pursue non-IVF fertility treatments, and therefore the present study sought to fill the gaps in the literature by evaluating the effect of depression and antidepressant use in couples pursuing non-IVF fertility treatments. Furthermore, we aimed to evaluate the effect of depression in the female partner as well as the male partner, which are not frequently reported together in the literature. We hypothesized that women and men with currently active major depression (MD) would have decreased fertility and poorer pregnancy outcomes compared with those without currently active MD, and that women using antidepressants who do not demonstrate currently active MD would have improved pregnancy outcomes compared with women continuing to have currently active depression, possibly depending upon the type of antidepressant used.

Continuous data are presented as mean ± SD. Categoric data are presented as n (%). Associations are presented as relative risk (RR) with 95% confidence interval (CI). A P value <.05 was considered to be statistically significant. Stata version 12 (Statacorp) was used for statistical analysis.

Bivariate analysis was conducted to examine the association between covariates and categories of female MD and antidepressant use and male MD. Parametric tests (Student t test, analysis of variance) were used to compare normally distributed data, nonparametric tests (Kruskal-Wallis) were used to compare nonnormally distributed data, and chi-square was used to compare proportions. Poisson regression models were subsequently constructed, adjusting for covariates that significantly differed between study groups as well as variables that have been previously demonstrated to affect outcome as identified in the literature. To assess the relationship between primary outcomes and female MD and antidepressant use, our model included age, race, income, months trying to conceive, current smoking, and study (PPCOS II vs AMIGOS). To avoid overcorrection, body mass index (BMI) was not included in the model owing to its significant correlation with study. Covariates used for analysis of female data by antidepressant use (and type) were the same, with the addition of PHQ-9 score to account for severity of depression. Poisson regression models were similarly used to assess the relationship between MD in the male partner and the primary outcomes adjusting for male age, BMI, and current smoking status and female age, antidepressant use, months trying to conceive, and PHQ-9 score. Power analysis revealed that our study had 80% power to detect a 14% difference in live birth rate for female subjects and a 22% difference in live birth rate for male subjects (alpha = 0.05; two-sided test).

The primary outcome tested was live birth. Secondary outcomes of interest included pregnancy and first-trimester pregnancy loss. First-trimester pregnancy loss was defined as cessation of pregnancy up to 13 weeks of gestation. Multigestation pregnancies with loss or reduction of one gestation but live birth of the other was classified as a live birth rather than a pregnancy loss. Live birth was defined as the delivery of a viable infant.

PHQ-9 scores were calculated for both partners. Currently active major depression (MD) was defined as PHQ-9 score ≥10. PHQ-9 scores and reported antidepressant use were used to stratify female subjects into four groups to account for the effect of currently active depression as well as the antidepressant: 1) no currently active MD, no antidepressant use; 2) no currently active MD, using an antidepressant; 3) presence of currently active MD, no antidepressant use; and 4) presence of currently active MD, using an antidepressant. Antidepressant use was then further stratified by the type of antidepressant used as follows: 1) no antidepressant use; 2) any antidepressant use; 3) only SSRI use; 4) only non-SSRI use; and 5) both SSRI and non-SSRI use.

In both trials, both partners completed the Patient Health Questionnaire (PHQ-9) at enrollment, which is a validated self-administered instrument that scores each of the nine Diagnostic and Statistical Manual of Mental Disorders, 4th edition, depression criteria as 0 (not at all) to 3 (nearly every day). Compared with the Mental Health Professional Interview as standard, a PHQ-9 score ≥10 has a sensitivity of 88% and specificity of 88% for MD. PHQ-9 scores of 5, 10, 15, and 20 represent mild, moderate, moderately severe, and severe depression, respectively (). Women were queried about medication use throughout both primary trials; however, data regarding medication use in the male partner was not collected during either study.

Institutional Review Board approval was obtained at all sites participating in each Reproductive Medicine Network trial. Female and male participants in the Pregnancy in PCOS II (PPCOS II) () and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) () randomized trials were included in this secondary analysis. Briefly, PPCOS II included 750 couples (female ages 18–40 years) in which the female partner was diagnosed with polycystic ovary syndrome (PCOS) by the presence of ovulatory dysfunction and either evidence of hyperandrogenism or polycystic ovaries on ultrasound, and without evidence of other infertility factors, including a sperm concentration of ≥14 million/mL in the male partner. Subjects were randomized to treatment with either clomiphene citrate (CC) or letrozole for ovulation induction. hCG testing was performed 2 weeks after the midluteal visit and was confirmed with serum testing. Pregnancy was defined as positive serum hCG level >10 mIU/mL. The AMIGOS trial included 900 couples (female ages 18–40 years) diagnosed with unexplained infertility (with a sperm concentration of ≥5 million/mL in the male partner) who were randomly assigned to ovarian stimulation with gonadotropins, CC, or letrozole in conjunction with intrauterine insemination (IUI). Study subjects underwent serum hCG testing two weeks after the date of IUI. Pregnancy was defined when hCG levels rose between two consecutive serum samples. For both studies, participants who conceived were followed until a viable intrauterine pregnancy was observed (fetal heart motion visualized with the use of ultrasound), and outcomes were tracked through delivery.

Sensitivity analysis was performed for male partner data and demonstrated that decreasing the PHQ-9 score cutoff to define currently active major depression weakened the association between depression and treatment outcome (pregnancy and live birth). This suggests that the worse the male depression, the worse the fertility treatment outcome.

Demographics of male subjects by MD status are presented in Table 1 . Unlike their female counterparts, there were no significant differences noted between men with or without currently active MD regarding age, BMI, smoking, study (AMIGOS vs. PPCOS II), or months trying to conceive. Furthermore, sperm concentration, female partner age, and female partner antidepressant use did not differ between the male subjects with and without currently active MD. However, the PHQ-9 score for female partners of men with currently active MD was higher than in female partners of men without currently active MD (female partner PHQ-9 score 4.24 vs. 2.61 (P=.002) for men with and without currently active MD, respectively), although the prevalence of currently active major depression in the female partner did not differ between groups (P=.06). The average PHQ-9 scores for men with and without currently active MD were, respectively, 13.41 ± 4.24 and 1.21 ± 1.83, and live birth rates were 8.82% and 24.67%. After adjusting for age, BMI, current smoking, months trying to conceive, female partner age, female partner PHQ-9 score, and female partner antidepressant use, male partners with currently active MD (n = 34) were less likely to have a partner achieve conception (RR 0.44, 95% CI 0.20–0.98; Table 4 ). It is notable that the pregnancy rates for men with currently active MD differed between studies (10.5% vs. 20% in AMIGOS and PPCOS II, respectively), although this difference did not reach statistical significance and is likely secondary to other associated factors that are intrinsic to a diagnosis of unexplained infertility.

Sensitivity analysis was performed with the use of various PHQ-9 score cutoffs to define currently active MD. Lowering the PHQ-9 cutoff to ≥5 to define currently active MD weakened the association between pregnancy and currently active MD, suggesting that the higher the PHQ-9 score, the more likely subjects were to conceive. A weakened association between miscarriage and the use of antidepressants in subjects without currently active MD was also observed. This suggests that subjects using an antidepressant whose depression was well controlled had a decreased risk of miscarriage compared with those not as well controlled.

Associations with antidepressant type are presented in Table 3 . The live birth rates for groups 1–5 were 24.93%, 23.33%, 28.07%, 8%, and 37.5%, respectively. Participants reporting any antidepressant use were more likely to experience a first-trimester loss compared with nonusers (RR 1.92, 95% CI 1.22–3.02). Specifically, the use of only non-SSRIs (n = 6) was associated with an increased risk of first-trimester loss (RR 3.45, 95% CI 1.99–5.98) compared with antidepressant nonuse, whereas use of only SSRIs was not associated with a statistically significantly lower live birth or pregnancy rate or increased first-trimester loss. Compared with those using only SSRIs, participants reporting use of a non-SSRI tended to have lower pregnancy (RR 0.45, 95% CI 0.21–1.00) and live birth (RR 0.16, 95% CI 0.02–1.10) rates, and increased pregnancy loss (RR 1.99, 95% CI 0.97–4.09), although these differences were not statistically significant.

Among women who were not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes; rather, the presence of currently active MD was associated with a slightly increased likelihood of pregnancy (RR 1.38, 95% CI 1.07–1.78; Table 2 ). In women without currently active MD, antidepressant use was associated with an increased likelihood of first-trimester loss (RR 1.87, 95% CI 1.18–2.99), an association that was not demonstrated in women with currently active MD. Despite these associations, there were no significant differences in live birth rates for any of the groups.

Covariates by female MD status and antidepressant use (group 1: no currently active MD, no antidepressant use; group 2: no currently active MD, using an antidepressant; group 3: presence of currently active MD, no antidepressant use; and group 4: presence of currently active MD, using an antidepressant) are presented in Table 1 . Significant differences among the groups were noted for age, BMI, months attempting conception, antimüllerian hormone, smoking status, income, and which study (PPCOS II vs. AMIGOS). Participants with currently active MD (groups 3 and 4) tended to have a higher BMI and were more frequently enrolled in the PPCOS II trial. When stratified by study and thus diagnosis (PPCOS II or AMIGOS, i.e., PCOS vs. unexplained infertility) there was a highly significant difference in the prevalence of currently active MD among our female subjects (11.02% vs. 1.63%, respectively; P

Note: Values are presented as mean ± standard deviation or n (%). AMH = antimüllerian hormone; AMIGOS = Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation; BMI = body mass index; PHQ-9 = Patient Health Questionnaire; PPCOS = Pregnancy in Polycystic Ovary Syndrome.

Demographics of female and male subjects by major depression status and antidepressant use in the female partner.

Table 1 Demographics of female and male subjects by major depression status and antidepressant use in the female partner.

Data were available for 1,650 women and 1,608 men, and PHQ-9 scores were available for 92% (n = 1,520) and 93% (n = 1,489) of those women and men, respectively. A majority of female subjects were white (79.52%), nulliparous (79.94%), highly educated (85.1% with at least some college education), nonsmokers (88.97%), with an average age of 30.68 ± 4.56 years and BMI 30.66 ± 8.88 kg/m 2 and had been trying to conceive for an average of 37.83 ± 31.82 months. The average PHQ-9 score for all female subjects was 2.8 ± 3.51, with 5.96% of women exhibiting currently active MD as defined as PHQ-9 score ≥10. Of all the female study participants, 5.72% indicated that they were using an antidepressant medication. A majority of women reporting antidepressant use scored <10 on the PHQ-9 (no currently active MD); however, 18.0% of women reporting antidepressant use met our criteria for currently active MD at the time of enrollment into the study. A majority of male subjects were white (77.7%), married (89.55%), highly educated (72.42% with at least some college education), nonsmokers (61.26%), with an average age of 33.02 ± 5.74 years and BMI 29.50 ± 6.57 kg/m 2 . The average PHQ-9 score for male subjects was 1.49 ± 2.65, with 2.28% of men exhibiting currently active MD. The presence of female partner with currently active MD, male partner with currently active MD, and antidepressant use did not differ between treatment groups within each individual study.

Discussion

In this study of infertile couples undergoing non-IVF fertility treatments, 5.96% of women had currently active MD and 5.72% used antidepressants. Approximately 2.28% of male partners had currently active MD. Women with currently active MD did not demonstrate lower pregnancy or live birth rates compared with women without currently active MD. Women taking antidepressants were at a higher risk of experiencing miscarriage, which was largely explained by the use of non-SSRI drugs. Partners of men with currently active MD were less likely to conceive.

3 Crawford N.M.

Hoff H.S.

Mersereau J.E. Infertile women who screen positive for depression are less likely to initiate fertility treatments. 6 Chen D.

Zhang J.P.

Jiang L.

Liu H.

Shu L.

Zhang Q.

et al. Factors that influence in vitro fertilization treatment outcomes of Chinese men: a cross-sectional study. 15 Kroenke K.

Spitzer R.L.

Williams J.B.W. The PHQ-9: validity of a brief depression severity measure. 16 Lewis A.M.

Liu D.

Stuart S.P.

Ryan G. Less depressed or less forthcoming? Self-report of depression symptoms in women preparing for in vitro fertilization. 3 Crawford N.M.

Hoff H.S.

Mersereau J.E. Infertile women who screen positive for depression are less likely to initiate fertility treatments. 6 Chen D.

Zhang J.P.

Jiang L.

Liu H.

Shu L.

Zhang Q.

et al. Factors that influence in vitro fertilization treatment outcomes of Chinese men: a cross-sectional study. 3 Crawford N.M.

Hoff H.S.

Mersereau J.E. Infertile women who screen positive for depression are less likely to initiate fertility treatments. The prevalence of depression was lower in this infertile cohort than expected. Previously published studies have demonstrated up to 41% prevalence of depression in women seeking fertility treatment () and 49.1% prevalence in men undergoing IVF treatment (). Factors that could account for the variations in reported prevalences include the use of different methods of measuring and quantifying symptoms of depression. The present study used the PHQ-9 score, which has been shown to have 88% sensitivity and 88% specificity for detection of MD (). Similarly, another study using the PHQ-9 score to assess infertile women preparing to undergo IVF reported a low prevalence of major depression (2%) with the use of a PHQ-9 score of ≥10 for classification; data were not collected for male partners (). There are several other depression screening methods reported in studies assessing infertile populations, with the highest prevalence of depression noted in studies using the National Institutes of Health Patient-Reported Outcome Measurement Information System (PROMIS) screening tool (41% prevalence of depression in female subjects []) and the Self-Rating Depression Scale (49.1% prevalence of depression in male subjects []). It is also possible that the difference in prevalence is due to differing patient populations rather than as a result of the screening tool itself. Furthermore, it has been demonstrated in the literature that women who screened positive for depression were significantly less likely to pursue fertility treatments (OR 0.55, 95% CI 0.31–0.95) () and therefore may also be less likely to enroll in a fertility treatment study. Finally, it may be that enrolling in a study that provides fertility treatments without cost decreases stress and therefore has a positive impact on depression.

17 Pasch L.A.

Gregorich S.E.

Katz P.K.

Millstein S.G.

Nachtigall R.D.

Bleil M.E.

et al. Psychological distress and in vitro fertilization outcome. 18 Matthiesen S.M.S.

Frederiksen Y.

Ingerslev H.J.

Zachariae R. Stress, distress and outcome of assisted reproductive technology (ART): a meta-analysis. 19 Boivin J.

Griffiths E.

Venetis C.A. Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies. 20 Casilla-Lennon M.M.

Meltzer-Brody S.

Steiner A.Z. The effect of antidepressants on fertility. 21 Nillni Y.I.

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. 22 Sejbaek C.S.

Hageman I.

Pinborg A.

Hougaard C.O.

Schmidt L. Incidence of depression and influence of depression on the number of treatment cycles and births in a national cohort of 42 880 women treated with ART. 4 Cesta C.E.

Viktorin A.

Olsson H.

Johansson V.

Sjölander A.

Bergh C.

et al. Depression, anxiety, and antidepressant treatment in women: association with in vitro fertilization outcome. 17 Pasch L.A.

Gregorich S.E.

Katz P.K.

Millstein S.G.

Nachtigall R.D.

Bleil M.E.

et al. Psychological distress and in vitro fertilization outcome. Our study did not demonstrate decreased pregnancy or live birth rates in women with currently active MD. Similarly to our findings, a study of 202 women undergoing their first IVF procedure showed no difference in live birth rate in women with preprocedure depression (), and meta-analyses by Mathiessen et al. () and Boivin et al. () demonstrated no significant association between depression before beginning assisted reproductive technology (ART) treatment and clinical pregnancy rate or between emotional distress and ART outcomes. Compared with those studies, the present study was conducted in subjects undergoing non-IVF procedures only, which further supports the existing literature and suggests that the absence of poorer fertility treatment outcomes in the IVF literature is not due to the ability of IVF technology to overcome the effect of depression on fertility outcomes. Studies in noninfertile populations have reported similar results. A study of natural fertility in a noninfertile cohort did not demonstrate a decreased pregnancy rate in women reporting depression (). A similar population-based study evaluating the association between Major Depression Inventory (MDI) scores and fecundability did find an association between MDI score and self-reported fecundability, but only for women with severe depression (fecundability ratio [FR] 0.62, 95% CI 0.43–0.91) and not for women demonstrating mild (FR 1.00, 95% CI 0.79–1.26) or moderate (FR 0.94, 95% CI 0.69–1.28) depression (). Similarly, a study including only cases of depression requiring hospitalization (implying increased severity) reported lower mean number of live births after ART procedures compared with those without depression (). Therefore, variation in outcomes reported in the literature could be due to differences in the severity of depression, methods of pregnancy detection, inclusion of women with depression and anxiety (), and antidepressant use ().

21 Nillni Y.I.

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. 23 Domar A.D.

Friedman R.

Zuttermeister P. Distress and conception in infertile women: a complementary approach. 24 Demyttenaere K.

Bonte L.

Gheldof M.

Vervaeke M.

Meuleman C.

Vanderschuerem D.

et al. Coping style and depression level influence outcome in in vitro fertilization. 25 Frederiksen Y.

Farver-Vestergaard I.

Skovgard N.G.

Ingerslev H.J.

Zachariae R. Efficacy of psychosocial interventions for psychological and pregnancy outcomes in infertile women and men: a systematic review and meta-analysis. Interestingly, women with currently active MD who were not receiving antidepressant therapy had a slightly higher pregnancy rate compared with subjects without MD, but no difference in live birth rate. In the above-mentioned study assessing the association between MDI scores and fecundability (), the authors found that although severe depression was associated with decreased fecundability, when stratified by psychotropic medication use the subjects who were not currently receiving medications but had used them in the past did not have a lower pregnancy rate (FR 1.18, 95% CI 0.80–1.76), suggesting that previous treatment may improve pregnancy rates compared with those that were either never treated or who were currently receiving treatment. Unfortunately, the studies analyzed here did not directly assess previous antidepressant use, so the effect of previous use could not be determined. Furthermore, studies assessing nonpharmacologic treatments have demonstrated improvement in depression scores (), and a meta-analysis assessing the effect of psychosocial interventions for infertile couples with depressive symptoms, anxiety, infertility stress, and/or marital dysfunction found that psychosocial interventions for couples pursuing fertility treatments improved clinical pregnancy rates (). Data regarding nonpharmacologic treatments for depression, such as psychotherapy and mind-body programs, were not collected in the present studies, so the effect of these interventions could not be assessed.

12 Domar A.D.

Moragianni V.A.

Ryley D.A.

Urato A.C. The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health and beyond. The present study did not demonstrate an increase in pregnancy rate among women on antidepressant medication whose depression was well controlled (i.e., not currently active). This is similar to the findings outlined in a review by Domar et al. demonstrating that there were no statistically significant differences in pregnancy rates among women using SSRI medications in any of the studies under review (), although the majority were conducted in an IVF population. The findings of our study further support that antidepressant medications do not seem to improve fertility treatment outcomes even in the absence of IVF technologies.

11 Almeida N.D.

Basso O.

Abrahamowicz M.

Gagnon R.

Tamblyn R. Risk of miscarriage in women receiving antidepressants in early pregnancy, correcting for induced abortions. 26 Hemels M.E.H.

Einarson A.

Koren G.

Lanctôt K.L.

Einarson T.R. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. 27 Rahimi R.

Nikfar S.

Abdollahi M. Pregnancy outcomes following exposure to serotonin reuptake inhibitors: a meta-analysis of clinical trials. 4 Cesta C.E.

Viktorin A.

Olsson H.

Johansson V.

Sjölander A.

Bergh C.

et al. Depression, anxiety, and antidepressant treatment in women: association with in vitro fertilization outcome. This study did demonstrate an increased risk of first-trimester pregnancy loss among women treated with the use of antidepressants. This finding is consistent with multiple recent studies () and two meta-analyses () which demonstrated increased risk of spontaneous abortion (RR 1.45, 95% CI 1.19–1.77) in women using antidepressants. Unlike the meta-analyses, our study showed that increased risk of loss was associated only with non-SSRI use (and not with SSRI use). This suggests that perhaps the lack of consensus in the literature regarding antidepressant use and fertility outcomes may be due in part to nonstratification by antidepressant type. Cesta et al. showed that risk of miscarriage increased with non-SSRI dispensation within 6 months before IVF (OR 3.56, 95% CI 1.06–11.9) but not with SSRIs (). The authors of that study concluded that women on non-SSRI antidepressants likely had a more severe disorder and were more likely to continue taking the medication during pregnancy.

6 Chen D.

Zhang J.P.

Jiang L.

Liu H.

Shu L.

Zhang Q.

et al. Factors that influence in vitro fertilization treatment outcomes of Chinese men: a cross-sectional study. 28 Williams K.

Reynolds M.F. Sexual dysfunction in major depression. 29 Baldwin D.S.

Foong T. Antidepressant drugs and sexual dysfunction. 30 Fabre L.F.

Clayton A.H.

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Derogatis L.R. Association of major depression with sexual dysfunction in men. 31 Gelenberg A.J.

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Ninan P.T. Sexual functioning in patients with recurrent major depressive disorder enrolled in the PREVENT study. 32 Ishak W.W.

Christensen S.

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et al. Sexual satisfaction and quality of life in major depressive disorder before and after treatment with citalopram in the STAR*D study. 33 Corona G.

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et al. Frequency of sexual activity and cardiovascular risk in subjects with erectile dysfunction: cross-sectional and longitudinal analyses. 10 O’Connor E.

Rossom R.C.

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Burda B.U. Primary care screening for and treatment of depression in pregnant and postpartum women evidence report and systematic review for the US Preventive Services Task Force. 11 Almeida N.D.

Basso O.

Abrahamowicz M.

Gagnon R.

Tamblyn R. Risk of miscarriage in women receiving antidepressants in early pregnancy, correcting for induced abortions. Women with male partners with currently active MD were less likely to conceive following non-IVF fertility treatment, and this effect may vary by infertility diagnosis and severity of male depression. We found a non–statistically significant difference in conception rates in men with currently active MD between the studies (AMIGOS and PPCOS II). It is likely, however, that there are other factors affecting pregnancy rates in each of the studies, such as female infertility factors and innate differences in conception rates by infertility diagnosis, that likely have a larger effect than factors related to MD in male partners. Similarly, a study of Chinese men (n = 202) demonstrated that male depression was an independent predictor of IVF failure (). Depression may cause sexual dysfunction due to reduced libido, erectile dysfunction, or delayed or inhibited ejaculation (), with the incidence of symptoms being associated with the severity of depression (). A study of more than 2,000 men showed that intercourse frequency is decreased when depression is present in the male partner and that frequency decreases with severity (). Our sensitivity analysis also supports that fertility treatment outcomes may be poorer in men with currently active depression that is more severe. It is possible that intercourse frequency may contribute to the differences in fertility treatment outcomes seen in the present study; however, our subjects were instructed to have intercourse two to three times per week (PPCOS II) or underwent intrauterine insemination procedures (AMIGOS). Alternatively, depression and antidepressant use may negatively affect sperm parameters, including concentration, motility, morphology, and DNA integrity (). We did not observe significant differences in sperm concentration between men with or without currently active MD; however, we did not collect data on sperm morphology, DNA integrity, or male antidepressant use.

The present study does have limitations. It was a secondary analysis of two randomized controlled trials that included different populations of subjects (PCOS vs. unexplained infertility). Combining data from two patient populations, however, potentially makes our findings more generalizable. Data regarding other, i.e., nonpharmacologic, treatments for depression and indication for antidepressant use in women are lacking in our study, as well as information on use of treatments for depression in the male partner. The absolute difference in live birth rate for men with currently active MD was 15.85%; however, our study was only powered to detect a 22% difference. Although a difference in miscarriage rate was noted in women using non-SSRIs, the number of subjects was low (n = 6), so definitive conclusions can not be made. The strengths of this study include the use of two multicenter studies with large sample sizes, prospective collection of outcomes after assessment of MD at baseline, collection of data on MD for both partners, and adequate power to detect a clinically meaningful difference in live birth rate for women with currently active MD.