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By considering the reasons behind discontinuing assisted reproductive technology (ART) treatment, several studies have indicated that ‘stress’ is an important issue, but the prevalence of stressors and stress responses, either acute or chronic, remains unclear. In this systematic review, we evaluated the characteristics, prevalence and causes of what was perceived and reported as ‘stress’ by couples who discontinued ART treatment. Electronic databases were systematically searched, and studies were considered eligible if they evaluated stress as a possible reason for ART discontinuation. Twelve studies were included, with 15,264 participants from eight countries. In all studies, ‘stress’ was assessed through generic questionnaires or medical records, not by validated stress questionnaires or biomarkers. The prevalence of ‘stress’ ranged from 11–53%. When the results were pooled, ‘stress’ was cited as a reason for ART discontinuation by 775 out of 2507 participants (30.9%). Clinical factors associated with worse prognosis, physical discomfort due to treatment procedures, family demands, time pressure and economic burden were identified as sources of ‘stress’ that contributed to ART discontinuation. Precisely knowing the characteristics of the stress associated with infertility is essential to devise preventive or supportive interventions to help patients to cope and endure the treatments. Further studies are necessary to investigate whether the mitigation of stress factors can reduce ART discontinuation rates.
). Assisted reproductive technology (ART) offers new hope for infertile persons and couples to become biological parents, particularly when oocytes are collected before ovarian ageing (
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
). Dropout is an important failure cause in ART, as pursuing several treatment cycles can triple the chance of a live birth compared with a single cycle (
Can repeat IVF/ICSI cycles compensate for the natural decline in fertility with age? an estimate of cumulative live birth rates over multiple IVF/ICSI cycles in Chinese advanced-aged population.
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
). Physiologically, stress is defined as an exacerbated, energy-expending response to an environmental event, generated by a threat or by an anticipated threat to organism integrity, whether real or perceived, psychological or physical (
). This environmental event is commonly called a stressor or stress factor, whereas reactions to factors are termed stress responses (Figure 1). This response is quite complex and induces neurological and metabolic alterations, with central and peripheral repercussions. The stress response starts in the hypothalamus and the brainstem, where specialized neurones produce corticotrophin-releasing hormone and arginine-vasopressin, as well as the locus coeruleus and other central areas that release noradrenaline. The response reaches peripheral organs by endocrine (adrenocorticotropic hormone) and neural (sympathetic) pathways (
in: Feingold KR Anawalt B Boyce A Chrousos G De Herder WW Dhatariya K Dungan K Hershman JM Hofland J Kalra S Kaltsas G Koch C Kopp P Korbonits M Kovacs CS Kuohung W Laferrere B Levy M Mcgee EA Mclachlan R Morley JE New M Purnell J Sahay R Singer F Sperling MA Stratakis CA Trence DL Wilson DP Endotext. 2000
Figure 1Left: examples of stressors (stress factors) cited by women and couples who discontinued assisted reproductive technology treatments; centre: the stress response driven by the hypothalamus–pituitary–adrenal axis; right: acute and chronic stress symptoms that can be assessed through objective questionnaires (adapted from
in: Feingold KR Anawalt B Boyce A Chrousos G De Herder WW Dhatariya K Dungan K Hershman JM Hofland J Kalra S Kaltsas G Koch C Kopp P Korbonits M Kovacs CS Kuohung W Laferrere B Levy M Mcgee EA Mclachlan R Morley JE New M Purnell J Sahay R Singer F Sperling MA Stratakis CA Trence DL Wilson DP Endotext. 2000
An acute stress factor, such as receiving an infertility diagnosis, activates the sympathetic nervous system and the hypothalamus–pituitary–adrenal axis, which normally prepares individuals for adverse situations (
). When situations are prolonged, such as years of unsuccessful fertility treatment, an inability to cope may produce a chronic stress state that triggers a catabolic process and causes cell and organ damage (
). This state can be distinguished from other psychological phenomena, like anxiety and depression. This is because chronic stress produces a predominantly somatic condition with marked endocrine and autonomic responses (
) and mitigation of the main stressors. The assessment of chronic stress, however, should ideally include objective scales of physical symptoms and measurement of biomarkers of the stress response (
in: Feingold KR Anawalt B Boyce A Chrousos G De Herder WW Dhatariya K Dungan K Hershman JM Hofland J Kalra S Kaltsas G Koch C Kopp P Korbonits M Kovacs CS Kuohung W Laferrere B Levy M Mcgee EA Mclachlan R Morley JE New M Purnell J Sahay R Singer F Sperling MA Stratakis CA Trence DL Wilson DP Endotext. 2000
). Without knowing precisely what people who discontinue ART mean by ‘stress’, it is difficult to devise preventive or supportive interventions to help them to cope and endure the treatments. In this systematic review, we evaluated the characteristics, prevalence and causes of what was perceived and reported as ‘stress’ by couples who discontinued ART treatment.
Materials and methods
This study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (
) and was registered in the International Prospective Register of Systematic Reviews database (PROSPERO, reference CRD42020210932). The electronic bibliographic search was conducted using the databases PubMed/MEDLINE and Scopus. The search terms used were as follows: (‘ART’ OR ‘in-vitro fertilization’ OR ‘IVF’) AND stress NOT oxidative AND (dropout OR abandon OR discontinuation OR interruption). A comprehensive examination of reference sections in articles was also carried out to identify relevant manuscripts.
The types of study eligible for inclusion were cohort, case-control, cross-sectional and case series. Additional inclusion criteria were as follows: individuals undergoing ART; discontinuation of ART treatment as an outcome; ‘stress’ as a cause of ART discontinuation; and publication in English. Exclusion criteria were as follows: non-human studies, review articles, case reports and full-text unavailability.
Two research qualified reviewers (ES and SNF) independently read titles and abstracts of retrieved articles using a predefined search strategy and applied study criteria. Selected full texts were read by the same authors and then independently by two other authors (LCT and MC), using the same pre-established criteria. Any disagreements regarding article inclusion or exclusion were discussed until a consensus was reached. Then, data were extracted from selected studies independently by two reviewers. Data extraction included study design and type of questionnaire, participant numbers and characteristics, definition of ART discontinuation, reasons for discontinuing treatment and stress measure.
The methodological quality of selected studies was assessed by two reviewers according to Newcastle–Ottawa Scale (NOS) criteria for case-control, cohort and cross-sectional studies. This scale consisted of three criteria: selection of participants; comparability of study groups; and verification of exposure (for case-control studies) or outcome of interest (for cohort and cross-sectional studies). The score was measured using a star system in which each study could receive 0–9 stars, with a maximum of four stars for the selection category, two for comparability and three for outcome or exposure. The score, or number of stars, was converted to the Agency for Health Care Research and Quality standard, which permitted study classification as poor, fair or good quality (
Variation of effect estimates in the analysis of mortality and length of hospital stay in patients with infections caused by bacteria-producing extended-spectrum beta-lactamases: a systematic review and meta-analysis.
Database and manual searches returned 109 non-duplicated articles, of which 97 did not meet inclusion criteria or were excluded for several reasons (Figure 2). Finally, 12 articles were selected for this review (
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
Selected studies evaluated 15,264 participants from eight countries. The average age of women was 34 years, mean infertility duration was 5.7 years, and mean number of treatment cycles for each couple was 2.1. Of the 12 articles, eight were cohort studies (seven were retrospective), one was a case-control study and three were cross-sectional studies (Table 1). For inclusion criteria, four studies (
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
), whereas the remaining 10 studies used prospective questionnaires completed by participants (email, telephone or interview methods). Ten studies used structured questionnaires (multiple choice of Likert-type scale), whereas two asked open questions (Table 1).
Results summary
As shown in Table 2, ‘stress’ or some proxy term was cited as a reason for ART discontinuation by 775 out of 2507 participants (pooled prevalence = 30.9, range 11–53%). In all included studies, stress evaluation was subjective and self-reported or based on the retrospective review of annotations in medical records. None of the studies used objective scales to measure stress symptoms or laboratory tests to quantify stress biomarkers (Table 2).
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
In terms of the primary sources of stress during ART treatment, a structured questionnaire answered by 127 women from one IVF centre in the USA highlighted ‘infertility taking too much of a toll on our relationship’; ‘too anxious or depressed to continue’; ‘it was too difficult to get to the IVF centre so often’; ‘I had already given IVF my best chance’; and ‘could not stand the side-effects of medication’ (
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
), according to scale conversion thresholds of Agency for Health Care Research and Quality standards (Supplementary Table). Consensus was reached on all occasions, and no study was excluded from this review based on the risk of bias.
Discussion
Main findings
In this systematic review, we found that ‘stress’ was mentioned by a high proportion (>30%) of patients who terminated ART treatments, but quantifiable stress signs, symptoms and biomarkers were not assessed. Clinical factors associated with worse prognosis, physical discomfort caused by treatment procedures, family demands, time pressure and economic burden were identified as ‘stress’ factors arising during ART treatment. The included studies had different designs but most used structured questionnaires, whereas two applied open questionnaires in which patients spontaneously reported their reasons behind ART discontinuation.
Interpretation
Woman's age, together with the number of recovered oocytes and the number of viable embryos for transfer, are determining elements of the success or failure of the treatment (
). In this context, advanced age per se is a source of stress in these patients, which is aggravated in those with diminished ovarian reserve. Fertility preservation through oocyte vitrification is an alternative to ‘stop the clock’ and reduce time pressure on patients who need to postpone gestation. Female fertility preservation, however, still requires complex, expensive, and sometimes painful procedures, which can be stressful.
Couples with fertility problems may experience a state of mental suffering derived from the uncertainties and demands that come with the clinical condition and treatments (
). Facing childlessness can be traumatic and challenging, particularly when dealing with feedback from family and friends.
The final decision to terminate treatment may be driven by unrealistic expectations of success and the inability to deal with treatment failure. Many couples enter treatment confidently but end up succumbing to despair after repeated unsuccessful IVF cycles. The realization that live birth rates are typically below 50% per ART cycle, added to the high cost of treatment, contributes to further increase the psychological stress of patients (
). Financial cost is a relevant stress factor for many individuals because, in many health systems of different countries, ART treatments are not insured (
A strength of the present systematic review is that the studies evaluated were fairly homogeneous in objectives, inclusion criteria, discontinuity definitions, data collection tools and outcomes. The overall response rate in studies was high, which provided a broad dataset for analysis. The main limitation of our systematic review is the lack of studies with a robust method to assess and quantify the stress experienced by the participants. Notably, none of the studies evaluated the stress response with objective scales or biomarkers, and all relied on what the participants themselves perceived as ‘emotional stress’. The selected studies, although identifying probable associations between stress and ART discontinuation, did not evaluate if stress reduction interventions decreased ART discontinuation rates.
Conclusion and perspectives
In summary, about one-third of the individuals who decide to discontinue ART treatments attribute their decision to the ‘stress’ associated with treatment failure (or the fear of failing), physical discomfort, family pressure, time constrains and economic burden. As some of these factors cannot be avoided, psychological support may help infertile couples cope with stress and mitigate their psychological suffering (
Exploratory randomized trial on the effect of a brief psychological intervention on emotions, quality of life, discontinuation, and pregnancy rates in in vitro fertilization patients.
). Patients should be well informed, given the opportunity to discuss treatment concerns, and receive guidance on possible negative outcomes. New randomized controlled trials should investigate whether stress-reducing interventions might prevent early dropouts, thereby improving cumulative live birth rates in ART treatments.
Exploratory randomized trial on the effect of a brief psychological intervention on emotions, quality of life, discontinuation, and pregnancy rates in in vitro fertilization patients.
Can repeat IVF/ICSI cycles compensate for the natural decline in fertility with age? an estimate of cumulative live birth rates over multiple IVF/ICSI cycles in Chinese advanced-aged population.
Dropout rate and cumulative birth outcomes in couples undergoing in vitro fertilization within a funded and actively managed system of care in New Zealand.
Variation of effect estimates in the analysis of mortality and length of hospital stay in patients with infections caused by bacteria-producing extended-spectrum beta-lactamases: a systematic review and meta-analysis.
in: Feingold KR Anawalt B Boyce A Chrousos G De Herder WW Dhatariya K Dungan K Hershman JM Hofland J Kalra S Kaltsas G Koch C Kopp P Korbonits M Kovacs CS Kuohung W Laferrere B Levy M Mcgee EA Mclachlan R Morley JE New M Purnell J Sahay R Singer F Sperling MA Stratakis CA Trence DL Wilson DP Endotext. 2000
Fernando M Reis is Professor of Gynaecology and Reproductive Medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, and has been Visiting Professor at the universities of Siena and Paris. His research background includes reproductive physiology, stress response and infertility.
Key message
Clinical factors associated with worse prognosis, physical discomfort caused by treatment procedures, family demands, time pressure and economic burden were identified as sources of ‘stress’ that contributed to assisted reproductive technology discontinuation.
Article info
Publication history
Published online: February 01, 2023
Accepted:
January 24,
2023
Received:
December 29,
2022
Declaration: The authors report no financial or commercial conflicts of interest.
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