Infertility-related Stress and the Risk of Antidepressants Prescription in Women

A 10-year Register Study

Juliana Pedro; Ditte Vassard; Gritt Marie Hviid Malling; Charlotte Ørsted Hougaard; Lone Schmidt; Mariana Veloso Martins


Hum Reprod. 2019;34(8):1505-1513. 

In This Article

Abstract and Introduction


Study Question: Is the first-time redeemed prescription of antidepressants predicted by the level of infertility-related stress in women seeking ART treatment?

Summary Answer: Infertility-related stress in the personal and marital domains and general physical stress reactions were significant predictors of a first redeemed prescription of antidepressants after ART treatment in this 10-year follow-up cohort study.

What is Known Already: The literature has found inconsistent findings regarding the association between infertility-related stress and later psychological adjustment in fertility patients. The association between infertility-related stress and later prescription of antidepressants had never been explored in long-term cohort studies.

Study Design, Size, Duration: All women (n = 1169) who participated in the Copenhagen Cohort Multi-centre Psychosocial Infertility (COMPI) cohort study in the year 2000 (questionnaire data) were linked with the register-based Danish National ART-Couple (DANAC) I cohort, which includes women and their partners having received ART treatment from 1 January 1994 to 30 September 2009. The study population were among other national health and sociodemographic registers further linked with the Danish National Prescription Registry.

Participants/Materials, Setting, Methods: Women initiating ART treatment were followed until they had redeemed the first prescription of antidepressants or until 31 December 2009. Logistic regression analyses were conducted to test the association between general physical stress reactions and infertility-related stress in the personal, marital and social domains, respectively, and a future redeemed prescription of antidepressants. Age, education level, marital status, number of fertility treatments prior to study inclusion and female infertility diagnosis were included as covariates in the adjusted analyses. Further, the analysis was stratified according to childbirth or no childbirth during follow-up.

Main Results and the Role of Chance: The final sample consisted of 1009 women with a mean age of 31.8 years. At study inclusion, women had tried to conceive for an average of 3.45 years. At 10-year follow-up, a total of 13.7% of women had a first redeemed prescription of antidepressant medication. The adjusted odds ratio (OR) showed that high general physical stress predicted the later prescription of antidepressants (adjusted (adj) OR = 2.85, 95% confidence interval (CI) 1.96–4.16). Regarding infertility-related stress domains, high personal stress (adj OR = 2.14, 95% CI 1.46–3.13) and high marital stress (adj OR = 1.80, 95% CI 1.23–2.64) were significantly associated with the later prescription of antidepressants. Social stress was not significantly associated with the future redeemed prescription of antidepressants (adj OR = 1.10, 95% CI 0.76–1.61). Among women not having achieved childbirth during follow-up, the risk of a first-time prescription of antidepressants associated with infertility-specific stress was higher compared to the risk among women having childbirth during follow-up.

Limitations, Reasons for Caution: This study did not account for potential mediating factors, such as negative life events, which could be associated with the prescription of antidepressants. Second, we are not able to know if these women had sought psychological support during follow-up. Additionally, antidepressants might be prescribed for other health conditions than depressive disorders.

Wider Implications of the Findings: Our results suggest that women presenting high infertility-related stress in the personal and marital domains were at higher risk of redeemed first-time prescription of antidepressants after ART, independently of having delivered a child or not after initiation of ART treatment. Women would benefit from an initial screening specifically for high infertility-related stress. The COMPI Fertility Problem Stress Scales can be used by clinical staff in order to identify women in need of psychological support before starting ART treatments.

Study Funding/Competing Interest(s): This study was supported by the Portuguese Foundation for Science and Technology (FCT) under an individual doctoral grant attributed to the first author (SFRH/BD/103234/2014). The establishment of the DANAC I cohort was funded by Rosa Ebba Hansen's Fund. The COMPI Infertility Cohort project was supported by The Danish Health Insurance Fund ( 11/097–97), the Else and Mogens Wedell-Wedellsborgs Fund, the manager E. Danielsens and Wife's Fund, the merchant L.F. Foghts Fund, the Jacob Madsen and Wife Olga Madsens Fund. The authors have no conflicts of interest.


Extensive evidence has shown support for the psychological and social impact of infertility on women, men and couples. Some studies documented poor psychological adjustment to infertility diagnosis (for a review see Luk and Loke, 2015) and to fertility treatments (e.g. Boivin and Takefman, 1995; Klonoff-Cohen et al., 2001; Williams et al., 2007; Moura-ramos et al., 2010; Vahratian et al., 2011; Wichman et al., 2011). Longitudinal studies have shown that female depression seems to increase after unsuccessful treatment (Verhaak et al., 2007). A recent systematic review and meta-analysis found that patients with failed treatments and who ended treatment without achieving parenthood presented poor mental health (Pasch et al., 2012; Gameiro et al., 2014; Gameiro and Finnigan, 2017); however this adjustment tended to improve with time since treatment (Gameiro and Finnigan, 2017). A register-based study in Denmark found that women engaged in ART treatments with no live birth had a lower risk of being clinically diagnosed by a psychiatrist with a unipolar depression compared to those with live birth, as delivery is a risk factor for depression post-partum (Sejbaek et al., 2015). However, a Swedish cross-sectional study found that 20–23 years after IVF women were at increased risk of depression, especially those who remained childless and/or without a partner (Vikström et al., 2015). Another study found that women treated for infertility had less psychiatric disorders than controls (Yli-Kuha et al., 2010).

Antidepressant use has been increasing in the majority of European countries (OECD, 2013). Antidepressants prescription is used for moderate to severe depressive disorder, but also for other conditions such as anxiety, insomnia, panic disorders and neuropathic pain (Sindrup et al., 2005; Wong et al., 2016). In the field of fertility care, ~30% of women engaged in ART treatments fulfill criteria for mental health disorders (Volgsten et al., 2008) and 41% for depression in particular (Crawford et al., 2017) based on self-report evaluations. Women reporting higher depression did not seek medical advice for infertility to a similar extent as women without depression (Herbert et al., 2010; Crawford et al., 2017), and they initiated fewer ART treatment cycles and had a lower number of live births compared to those without a clinical depression diagnosis (Sejbaek et al., 2013). Although the use of antidepressants in women undergoing IUI treatment was not associated with pregnancy rates, it was associated with increased risk of pregnancy loss (Evans-Hoeker et al., 2018). The only study investigating antidepressant use among patients undergoing IVF found that the diagnosis of depression and the treatment with antidepressants before IVF was associated with reduced pregnancy rates (Cesta et al., 2016). This is of particular relevance since antenatal depression is associated with increased risk of postpartum depression, which has negative consequences for the woman's and child's health (Rwakarema et al., 2015). Post-partum depression can negatively influence the mother–child relationship, and the use of antidepressants during pregnancy and breastfeeding has been associated with increased risk for poor child development (Brummelte and Galea, 2016). In addition, a history of previous unsuccessful treatments seems to be associated with a higher risk of depressive symptomatology during pregnancy and after delivery (Agostini et al., 2018). Even though the risk of postpartum depression is not higher in women undergoing IVF, there is an increased risk in the case of previous history of mental illness (Vikström et al., 2017). Acting in a preventive way might diminish the negative influence of psychological strain on reproductive outcomes as well as preventing the negative consequences of depression for women and their children. Given the importance of prevention and early detection of psychosocial issues in people undergoing fertility treatments, knowing the link between pre-levels of stress and specifically infertility-related stress and future antidepressants prescription is crucial. This will be of great value since screening for stress at the beginning of treatment will enable fertility staff to understand patient needs and offer additional care accordingly, creating an opportunity to act in a preventive way and thus restrain the need for antidepressants. The majority of studies investigating the predictive role of infertility-related stress on later development of maladjustment has been focused on self-reported outcome measures (for a review see Rockliff et al., 2014). Self-reported mental health outcome measures can be biased by social desirability, i.e. study participants might answer what they think they are expected to state. In our study, we used register-based data on the first-time redeemed prescription of antidepressants as outcome, which can be considered an indicator of psychological strain. Around 90% of prescriptions of antidepressants in Denmark are managed in primary health care (general practitioners) and the remaining 10% in secondary care (psychiatrists at hospitals) (Eplov et al., 2005). By using prescription data, we were able to include minor or moderate depression and not only the most severe depressions diagnosed and treated by a psychiatrist.

The present study aims to explore the predictive role of general physical stress and more specifically the role of infertility-related stress when initiating ART treatment, on the risk of a later first-time redeemed prescription of antidepressants in a 10-year follow-up cohort study of women initiating ART treatment in the year 2000–2001 in Denmark. In addition, since the literature showed contradictory findings regarding the link between achieving childbirth or not and later psychological strain, knowing if having a child influences the relation between infertility stress and the later prescription of antidepressants would help to clearify this question.