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How does stress, depression and anxiety affect patients undergoing treatment?

Boivin, Jacky

Current Opinion in Obstetrics and Gynecology: June 2019 - Volume 31 - Issue 3 - p 195–199
doi: 10.1097/GCO.0000000000000539
FERTILITY, IVF AND REPRODUCTIVE GENETICS: Edited by Emre Seli and Juan A. García Velasco
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SDC

Purpose of review To review latest findings about the impact of fertility care on emotional distress and effect of distress on treatment outcome.

Recent findings Treatment failure and long agonist protocols are associated with increased emotional distress during treatment. Screening tools can be used to identify men and women at risk of emotional maladjustment at the start of fertility treatment and people unlikely to need emotional support during or after treatment. There are inconclusive results about the association between emotional distress and outcome of fertility treatment. Systematic review of studies evaluating the effect of psychological and educational interventions on anxiety, depression and live birth (or ongoing pregnancy) are uninformative because of clinical heterogeneity and risk of bias.

Summary ART is emotionally demanding, patients that adapt more poorly can be identified in advance. Fertility staff should follow good practice guidelines to provide patients with support during treatment.

Cardiff Fertility Studies Research Group, School of Psychology, College of Biomedical and Life Sciences, Cardiff University, Cardiff, Wales, United Kingdom

Correspondence to Jacky Boivin, Cardiff Fertility Studies Research Group, School of Psychology, College of Biomedical and Life Sciences, Cardiff University, 70 Park Place, Cardiff, Wales CF10 3AT, United Kingdom. Tel: +44 2920 875 289; e-mail: boivin@cardiff.ac.uk

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INTRODUCTION

Managing emotional distress [anxiety, depression, perceived (infertility) stress] is an important aspect of fertility care. Increasingly, this type of psychosocial care is expected to be evidence-based, and provided by fertility clinic staff through patient-centred care, and not just referral to specialized counsellors [1▪,2▪]. This selective review will examine recent psychological studies that inform on provision of psychosocial care.

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INFERTILITY, INFERTILITY TREATMENT AND EMOTIONAL DISTRESS

Emotional distress in infertility patients has been attributed to the unfulfilled wish for a child, stigma of underlying conditions (e.g. hirsutism), limiting physical aspects (e.g. severe pelvic pain), treatment procedures (e.g. ovarian stimulation) and treatment events (waiting for pregnancy test) [3▪]. Two systematic reviews confirm past research in showing the effect of treatment failure on wellbeing of men and women ([4,5], both 12 studies). In addition to showing effects in women, these also showed that men's psychological adjustment could deteriorate during fertility treatment [5] especially in response to treatment failure [5]. Avoidance, catastrophizing and poor partner support was associated with poor adjustment in men [5]. Depression and anxiety lessened over time [4] with a return to baseline probably occurring between 6 [5] and 12 months [4] after fertility care. Toftager et al.[6] reported physical (feeling bloated, abdominal pain), emotional (e.g. unexpected crying) and behavioural (e.g. poor quality sleep) symptoms were more likely and intense in women randomly assigned to long gonadotrophin agonist (LGA) protocols than short antagonist protocols. This extra burden could explain why patients having up to three natural-cycle ART reported more satisfaction with treatment and less depression after treatment than patients having undergone a single cycle with LGA [7].

One important source of heterogeneity in studies on the impact of infertility treatment is measurement inconsistency. A recent Cochrane review reported the use of more than 30 different measures in the psychological literature aimed at improving wellbeing [8]. Using the same measure consistently could address this problem. Recently, a review [9▪▪] and an empirical study [10] examined the psychometric properties of the most frequently used measures of infertility-specific patient-reported outcomes (i.e. Fertility Quality of Life, FertiQoL [11], Fertility Problem Inventory, FPI [12], Copenhagen Multicentre Psychosocial Infertility-Fertility Problem Stress Scale, COMPI-FPSS [13]). Both studies concluded that the three measures had satisfactory psychometric properties [9▪▪,10]. There were advantages specific to each measure but equally there were gaps in psychometric testing for all measures, for example, lack of a clinically important difference [9▪▪]. Choice of tool should match the situation [9▪▪,10]. FertiQoL (24 items) is best for overall quality-of-life measurement, especially in treatment, is sensitive to the effects of interventions, and potentially useful for prediction of anxiety and depression. The Fertility Problem Inventory (34 items) is best for decision-making and longer term adjustment as it assesses beliefs known to be relevant to adapting to childlessness [14▪]. The COMPI-FPSS (14 items) is a coherent measure of perceived infertility stress and its brevity and link to the concept of stress make it useful for studies on stress, coping and clinical outcomes (e.g. pregnancy rate).

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EMOTIONAL DISTRESS AND ITS RELATIONSHIP TO TREATMENT OUTCOME

Many people think that emotional distress because of fertility problems or other stressors interferes with the success of fertility treatment. Although these beliefs are congruent with stress theories and nonhuman animal research, evidence in humans is not compelling.

Two recent systematic reviews and meta-analyses in ART samples (with overlapping studies) examined prospective studies on this association in ART. Nicoloro-SantaBarbara et al.[15▪] included 20 studies evaluating the association between anxiety, depression or perceived stress and verified pregnancy (blood test, ultrasound scan, live birth) in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Pooled effect sizes for anxiety or depression measured before or during treatment (four separate analyses) revealed nonsignificant effect sizes between outcome groups. A similar nonsignificant pooled effect size was obtained for perceived stress. None of the moderators were significant in explaining heterogeneity which ranged from 35 to 78%. In contrast, Purewal et al.[16,17▪] reported significant associations between treatment outcome and anxiety and depression measured pretreatment and during treatment in women undergoing ART. Meta-analysis of pretreatment data (22 studies) showed a small significant negative effect size (SMD) for depression and anxiety. Meta-analysis of emotional distress during treatment (from pretreatment to embryo transfer) (11 studies) also showed significant, negatively pooled effect sizes with effects being smaller when only IVF patients (not ICSI) and recent studies (since 2010) were considered. The difference in results requires explanation especially for distress during treatment where Purewal et al.[17▪] reported effect sizes double those reported in Nicolo-SantaBarbara et al.[15▪] despite similar study selection criteria.

Purewal et al.[17▪] included six additional studies and these generally had higher effect sizes than the other studies overlapping with that of Nicolo-SantaBarbara, making this a likely explanation for the difference in results. However, there were inexplicable choices in Purewal [17▪] too that could have produced larger effect sizes during treatment (e.g. allocation of a large ‘pretreatment’ effect size to ‘during treatment’ analysis). Even if effect sizes do prove to be of that size during treatment, it is unlikely that these would indicate that being stressed or distressed during treatment reduced the chance of pregnancy because of confounding. Ratings taken at oocyte retrieval or embryo transfer (i.e. during treatment) will strongly reflect knowledge about the quantity and quality of oocytes and embryos produced, which highly predict treatment outcome.

A lack of consistent association between meta-analyses could be because of the poor explanatory power of the simple associative model used, where emotional distress is the only risk factor considered. More complex models that take into account biomedical (e.g. prognostic indicators) and behavioural risk factors (e.g. smoking, caffeine) that vary with emotional distress could probably improve its prediction for treatment outcome. However, if complex models are developed, these should focus on risks that benefit ART outcomes when modified. A recent systematic review and meta-analysis [18▪▪] demonstrated that preconception lifestyle interventions based on caloric restriction and exercise were effective in stimulating weight loss (about 3.5 kg) and BMI status change (about one-point change) but these losses only produced a higher pregnancy rate in people achieving pregnancy without ART and not in those undergoing ART [18▪▪].

It has been argued that, in any case, supraphysiologic effects of stimulation and mechanical procedures of oocyte retrieval and embryo transfer would compensate for any effects of emotional distress on ART treatment outcome obscuring any true association between stress and fertility. However, even among infertile people in the general population (i.e. nonclinical sample) emotional distress is not associated with eventual pregnancy [19▪]. In a Norwegian registry study, infertile women from the general population with and without clinical levels of emotional distress were followed up to determine whether they would achieve pregnancy [19▪]. The results showed that 20.1% of women scored above the clinical cut-off for anxiety, 7.7% for depression, and 22.2% for either. Follow-up was complete (0% attrition because of register). The live birth rate was overall 28.7% and was not significantly different in women with clinical levels of emotional distress: 32.7% live birth in women with high anxiety, 33.0% high depression, 27.6% both high anxiety and depression). Authors counter-argued alternative explanations on the grounds of controlling confounders and power.

The two new meta-analyses do not provide clarity on the association between anxiety and depression in women undergoing ART.

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EARLY DETECTION OF EMOTIONAL DISTRESS

Early detection of emotional distress could help clinics provide preventive support at the start of treatment. The SCREENIVF was developed to identify people with emotional maladjustment before treatment and later during or after treatment outcome [20]. It detects risk based on ratings of depression, anxiety, helplessness, acceptance of infertility and social support. Past research showed that SCREENIVF had satisfactory sensitivity and specificity but this finding was based on using overlapping items in the detection and outcome tools, a limitation that could inflate predictive validity. The concurrent and predictive validity of the SCREENIVF was recently tested using different items in 913 Dutch men and women undergoing ART. SCREENIVF and emotional maladjustment (self-reported Hospital Anxiety and Depression Scale, HADS) were measured at the start of stimulation before the first scan [21▪▪]. The HADS was completed again 10 days and 6 weeks after embryo transfer (corresponding to waiting period for pregnancy test and postresults, respectively). Results showed that concurrent validity (cross-sectional prediction from SCREENIVF to HADS) was better than predictive validity (prospective prediction from SCREENIVF at start to HADS-day 10 or HADS-week 6). Furthermore, SCREENIVF was better at predicting those not at risk then those at risk of emotional maladjustment. These results mean that staff using SCREENIVF could feel confident that if patients were categorized as ‘not at risk’ at the start of treatment then it would be very unlikely that they would have emotional maladjustment later. However, staff should have less confidence that those rated as ‘at risk’ would have emotional maladjustment during those later periods. Poor prediction was attributed to low base rate for maladjustment in infertile populations. It was also attributed to the problem of missing predictors, namely pregnancy status at the predicted time of risk (e.g. 6 weeks after treatment outcome). To improve positive predictive values it was suggested that the SCREENIVF algorithm be adjusted to include prognostic indicators (e.g. age) [21▪▪].

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IMPACT OF INTERVENTION STUDIES ON EMOTIONAL DISTRESS IN PEOPLE WITH INFERTILITY

Supporting patients during treatment could improve wellbeing during treatment and counter any negative effects of emotional distress on treatment outcome and trajectory (if these exist). Several reviews have sought to synthesize this research but only recently was a Cochrane review carried out (Verkuijlen et al.[8]). The review examined psychological and educational interventions in infertility (39 RCTs, 4925 participants). The set of primary outcomes were anxiety, depression, live birth and ongoing pregnancy (20 weeks). Psychological interventions were named therapies (e.g. mind–body program) and therapies focused on changing behaviour, cognitions or emotional impact of infertility and fertility care. Educational interventions were geared toward improving self-management and self-efficacy (e.g. better coping) through education about infertility and its treatment and relevant psychosocial strategies (e.g. coping skills training, psychoeducation). The review concluded that data could not be pooled across intervention studies because of too high risk of bias (especially from lack of blinding and high attrition) and too high clinical heterogeneity in participant characteristics, nature of interventions and delivery characteristics. Indeed, all studies had high risk of bias on at least one domain, and 50% had risk of bias for blinding and attrition. Further, the included studies evaluated more than 25 different interventions (e.g. hypnosis, music therapy, cognitive behaviour therapy, stress management, informative leaflets) delivered in many ways. Summary data was presented for the primary outcomes but the authors warned that effects, especially benefits, should be considered with extreme caution as the biases ‘resulted in exaggerated and implausible odds ratios’ (Verkuijlen et al.[8], p. 26). Consequently, the evidence was generally downgraded to very low-quality evidence, and a plea made for more rigorous designs.

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CONCLUSION

Increasingly, fertility clinic staff will be called upon to provide evidence-based psychosocial care. To do so, they will require knowledge of the emotional impact of treatment, the effect emotional distress can have on treatment trajectories and outcomes, and the interventions staff can use to deliver psychosocial care within the constraints of their clinical duties. Three main themes emerged from this review. First, more rigorous and homogenous experimental designs are needed to improve quality of psychological research. Consistently using one of the infertility patient-reported outcomes (FertiQoL, Fertility Problem Inventory, COMPI-FPSS) and improving trial design in intervention evaluation studies (especially use of attentional control groups and follow-up) would help. Evaluation should be concentrated on replicating effects of existing, theory-driven psychological and educational interventions and mechanisms of action rather than on development of more interventions. Second, we need more research on the experiences of men in treatment because they too suffer from infertility and its treatment. Men are only partially represented in intervention studies (usually as part of couple), and virtually absent from research on the effect of emotional distress on treatment outcome and trajectories despite being integral for both. Third, the emotional demands of treatment and protocols are significant. Patients should be informed in advance of the burden of particular drug protocols and the period of emotional distress that ART could involve so they can integrate these in decision-making about treatment. Men should not be neglected in discussions of psychosocial implications of treatment. Finally, staff should screen people at the start of treatment (e.g. using SCREENIVF) to identify not only those already distressed at the start but also those unlikely to need additional support later on so psychosocial resources are directed to those that need it the most. The evidence base for effective interventions is not yet informative but psychosocial guidelines for fertility staff not specialized in psychosocial care exist [1▪] and these could be used to guide good practice until better quality evidence is published.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

J.B. (Cardiff University) has received funding from Merck Norway (Merck AB NUF) for the Norwegian translation of the Fertility Quality of Life (FertiQoL) tool and funding from Ferring International Center S.A. for the Czech translation of the FertiQoL scale. The employer of J.B. (Cardiff University) could one day receive royalties from the commercial use of Fertility Quality of Life (FertiQoL). J.B. could one day receive royalties from the commercial use of Fertility Quality of Life (FertiQoL). However, both of these are unlikely because FertiQoL is freely available for practice and research.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1▪. Gameiro S, Boivin J, Dancet E, et al. ESHRE guideline: routine psychosocial care in infertility and medically assisted reproduction—a guide for fertility staff. Hum Reprod 2015; 30:2476–2485.

Guidelines for psychosocial care for fertility staff. This is their link to resources to help staff deliver deliver psychosocial care: https://www.eshre.eu/guidelines-and-legal/guidelines/psychosocial-care-guideline.aspx).

2▪. Human Fertilisation and Embryology Authority (2019). Code of Practice. Human Fertilisation and Embryology Authority, London, UK. Available at: https://www.hfea.gov.uk/media/2609/june-2018-code-of-practice-9th-edition-draft.pdf. (Accessed 04 February 2019)

Code of Practice for the HFEA, separating out for the first time patient-centered care from psychosocial counselling.

3▪. Farquhar CM, Bhattacharya S, Repping S, et al. Female subfertility. Nat Rev Dis Primers 2019; 5:7.

Excellent primer for female subfertility (medical and psychological). Constitutes overview section of impact female infertility on quality of life.

4. Milazzo A, Mnatzaganian G, Elshaug AG, et al. Astute Health Study Group. Depression and anxiety outcomes associated with failed assisted reproductive technologies: a systematic review and meta-analysis. PloS One 2016; 11:e0165805.
5. Martins MV, Basto-Pereira M, Pedro J, et al. Male psychological adaptation to unsuccessful medically assisted reproduction treatments: a systematic review. Hum Reprod Update 2016; 22:466–478.
6. Toftager M, Sylvest R, Schmidt L, et al. Quality of life and psychosocial and physical well being among 1,023 women during their first assisted reproductive technology treatment: secondary outcome to a randomized controlled trial comparing gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist protocols. Fertil Steril 2018; 109:154–164.
7. Haemmerli Keller K, Alder G, Loewer L, et al. Treatment-related psychological stress in different in vitro fertilization therapies with and without gonadotropin stimulation. Acta Obstet Gynecol Scand 2018; 97:269–276.
8. Verkuijlen J, Verhaak C, Nelen WL, et al. Psychological and educational interventions for subfertile men and women. Cochrane Database Syst Rev 2016; 3:CD011034.
9▪▪. Kitchen H, Aldhouse N, Trigg A, et al. A review of patient-reported outcome measures to assess female infertility-related quality of life. Health Qual Life Outcomes 2017; 15:86.

Excellent review for those considering RCTs with industry as review adheres to FDA guidance about patient-reported outcomes.

10. Pedro J, Frederiksen Y, Schmidt L, et al. Comparison of three infertility-specific measures in men and women going through assisted reproductive technology treatment. J Health Psychol 2016; 1-12. DOI: 10.1177/1359105316678669. [Epub ahead of print].
11. Boivin J, Takefman J, Braverman A. The fertility quality of life (FertiQoL) tool: development and general psychometric properties. Hum Reprod 2011; 26:2084–2091.
12. Newton CR, Sherrard W, Glavac I. The Fertility Problem Inventory: measuring perceived infertility-related stress. Fertil Steril 1999; 72:54–62.
13. Schmidt L, Holstein BE, Boivin J, et al. High ratings of satisfaction with fertility treatment are common: findings from the Copenhagen Multicentre Psychosocial Infertility (COMPI) Research Programme. Hum Reprod 2003; 18:2638–2646.
14▪. Gameiro S, Finnigan A. Long-term adjustment to unmet parenthood goals following ART: a systematic review and meta-analysis. Hum Reprod Update 2017; 23:322–337.

Very detailed mixed-method review about the long-term impact of being childless. Informative model of what clinicians can do with patients at the end of treatment to support future adjustment.

15▪. Nicoloro-SantaBarbara J, Busso C, Moyer A, Lobel M. Just relax and you’ll get pregnant? Meta-analysis examining women's emotional distress and the outcome of assisted reproductive technology. Soc Sci Med 2018; 213:54–62.

Disentangles pretreatment and during-treatment effect sizes within same review.

16. Purewal S, Chapman SC, Akker OB. A systematic review and meta-analysis of psychological predictors of successful assisted reproductive technologies. BMC Res Notes 2017; 10:711.
17▪. Purewal S, Chapman SC, van den Akker OB. Depression and state anxiety scores during assisted reproductive treatment are associated with outcome: a meta-analysis. Reprod Biomed Online 2018; 36:646–657.

Carries out a range of sensitivity analyses to determine impact of decision-making on effect sizes; some decisions could be problematic.

18▪▪. Lan L, Harrison CL, Misso M, et al. Systematic review and meta-analysis of the impact of preconception lifestyle interventions on fertility, obstetric, fetal, anthropometric and metabolic outcomes in men and women. Hum Reprod 2017; 32:1925–1940.

Excellent systematic review of effects of specific lifestyle intervention. Examines range of outcomes so can be informative if used to counsel patients about how changes in risk can affect fertility.

19▪. Biringer E, Kessler U, Howard LM, et al. Anxiety, depression and probability of live birth in a cohort of women with self-reported infertility in the HUNT 2 Study and Medical Birth Registry of Norway. J Psychosom Res 2018; 113:1–7.

First study to examine relationship between emotional distress and eventual achievement of pregnancy in infertile women in the general population. Provides estimate of emotional distress in nonclinical infertile population.

20. Verhaak CM, Lintsen AM, Evers AW, Braat DD. Who is at risk of emotional problems and how do you know? Screening of women going for IVF treatment. Hum Reprod 2010; 25:1234–1240.
21▪▪. Ockhuijsen HD, van Smeden M, van den Hoogen A, Boivin J. Validation study of the SCREENIVF: an instrument to screen women or men on risk for emotional maladjustment before the start of a fertility treatment. Fertil Steril 2017; 107:1370.e5–1379.e5.

Very detailed analysis of SCREENIVF with specificity, sensitivity and positive and negative predictive values.

Keywords:

anxiety; depression; infertility; psychological intervention; screening

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