Open Access

A review of patient-reported outcome measures to assess female infertility-related quality of life

  • Helen Kitchen1Email author,
  • Natalie Aldhouse1,
  • Andrew Trigg1,
  • Roberto Palencia2 and
  • Stephen Mitchell3
Health and Quality of Life Outcomes201715:86

https://doi.org/10.1186/s12955-017-0666-0

Received: 16 August 2016

Accepted: 21 April 2017

Published: 27 April 2017

Abstract

Background

Infertility has a negative impact on quality of life (QoL) and well-being of affected individuals and couples. A variety of patient-reported outcome (PRO) measures to assess infertility-related QoL are available; however, there is a concern regarding potential issues with their development methodology, validation and use. This review aimed to i) identify PRO measures used in infertility interventional studies ii) assess validation evidence to identify a reliable, valid PRO measure to assess changes in QoL or treatment satisfaction in clinical studies with female patients following treatment with novel therapies iii) identify potential gaps in evidence for validity.

Methods

A structured literature search of Medline, Embase, and the Cochrane Library (accessed in September 2015) was conducted using pre-defined search terms. The identified publications were reviewed applying eligibility criteria to select interventional female infertility studies using PROs. Infertility-specific PRO measures assessing QoL, treatment satisfaction or psychiatric health, and included in studies by ≥2 research groups were selected and critically reviewed in light of scientific and regulatory guidance (e.g. FDA PRO Guidance for Industry) for evidence of content validity, psychometric strength, and patient acceptability.

Results

The literature search and hand-searching yielded 122 publications; 78 unique PRO measures assessing QoL, treatment satisfaction or psychiatric health were identified. Five PRO measures met the selection criteria for detailed review: Fertility Quality of Life (FertiQoL); Fertility Problem Inventory (FPI); Fertility Problem Stress (FPS); Infertility Questionnaire (IFQ); Illness Cognitions Questionnaire adapted for Infertility (ICQ-I). None of the PRO measures met all validation criteria. The FertiQoL was the most widely used infertility-specific PRO measure to assess QoL in interventional studies, with reasonable evidence for adequate content validity, psychometric strength, and linguistic validation. However, gaps in evidence remain including test-retest reliability and thresholds for interpreting clinically important changes. While the FPI demonstrated reasonable evidence for content and psychometric validity, its utility as an outcome measure is limited by a lack of recall period.

Conclusion

The FertiQoL and the FPI are potentially useful measures of infertility-related QoL in interventional studies. Further research is recommended to address gaps in evidence and confirm both PRO measures as reliable assessments of patient outcomes.

Keywords

Female infertility Quality of life Patient-reported outcomes Psychometric Validation

Background

Infertility is defined by the World Health Organisation (WHO) as “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse”[1], and is estimated to affect as many as 48.5 million couples worldwide [2]. Female infertility can be caused by many different factors including age which is a major determining factor [3], physiological dysfunction (this is also a factor in male, or couples infertility) [4], lifestyle (e.g. obesity, low body weight, smoking), and other unidentified causes [3]. Increasing evidence suggests that infertility represents a significant psychological burden to the affected individuals or couples as it can have a negative impact on their quality of life (QoL) and psychological and social well-being [59]. Furthermore, evidence suggests that women may be more substantially affected by infertility than their partners with respect to mental health, social functioning, and emotional behaviour [5, 10, 11].

Current infertility treatments such as surgical measures to treat genital tract obstruction or endometriosis, or hormone treatments to restore ovulatory function in women are aimed to reverse the primary causes of infertility; however, in cases where initial treatments are not successful or infertility is unexplained, assisted reproductive technology (ART), which includes in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), is the treatment of choice [3]. While infertility treatments are successful in a considerable proportion of cases [12], they often have a negative impact on the patients’ QoL. Hormone treatments may have various psychological side-effects and IVF treatment can be invasive, time consuming and stressful, further contributing to the overall burden of infertility [13, 14]. Thus, assessing the effects of novel infertility therapies on QoL from a patient perspective is important and may lead to improved patient outcomes [15, 16].

The World Health Organisation defines QoL as “individuals’ perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns”[17]. It is a broad ranging concept affected in a complex way by the person’s physical health, psychological state, level of independence, social relationships, personal beliefs and their relationship to salient features in the environment [17].

Quality of life can be assessed by using generic or disease-specific measures, with the latter being preferable as they include questions which focus on specific aspects of the condition [18]. The use of patient-reported outcome (PRO) measures specifically designed for the assessments of infertility-related QoL has gradually increased in the last decade [18], possibly as a result of clear regulatory standards which PRO measures employed in clinical trials must meet, and a recognised need to understand and assess patient’s wellbeing in clinical practice [1922]. Despite the availability of a variety of measures designed to assess infertility-related QoL of individuals or couples, there is still a concern regarding potential issues with the development methodology, validation and use of the existing PRO measures of infertility-related QoL [5, 15]. Given the importance of accurately assessing patient outcomes in relation to treatment and treatment satisfaction from a patient perspective, there is a need to identify robust, reliable, and validated PRO measures for use in clinical studies for the assessment of new infertility treatments.

The purpose of this research was therefore to identify reliable and valid PRO measures to assess changes in QoL or treatment satisfaction in clinical studies with female patients following treatment with novel therapies. The objectives of this structured literature review were to i) identify PRO disease-specific measures used in female infertility interventional studies ii) understand how PRO measures are used in infertility interventional studies, iii) identify and review the evidence that supports the validation of each PRO measure, and iv) identify any potential gaps in evidence for validity.

Methods

This research was conducted in two stages: i) identification of existing patient-reported outcome (PRO) measures used in female infertility interventional studies via a structured literature review; ii) detailed assessment of the most relevant PRO measures, according to specified selection criteria, for content validity (defined as the extent to which the instrument measures concepts of interest such as QoL, psychiatric health, treatment satisfaction [22]), psychometric performance (defined as an assessment of the measurement properties of the PRO measure [22]) and practical considerations (i.e. cross-cultural feasibility and burden to patient) on their usage in the intended population.

Identification of patient-reported outcome measures via structured literature review

The present structured literature review was conducted following a robust and reproducible methodology for the identification of relevant publications; a full protocol (not registered in a publicly available database) for the literature review was developed and executed to answer the objectives of this review.

The inclusion criteria were restricted to studies using disease-specific or generic PRO measures to determine the QoL of individuals affected by female factor infertility prior to, or while receiving infertility treatment. No restrictions were applied on type of intervention, comparator, country, language and date of publication of the studies. Further details about the eligibility criteria for study inclusion are available in the online supporting information (see Additional file 1: Table S1).

To identify relevant studies, the following databases were searched on 15th September 2015: MEDLINE (including MEDLINE in process, from 1946); Embase (1980–2015); The Cochrane Library (Evidence based medicine reviews in OVID) including: Cochrane Central Register of Controlled Trials August 2015, Cochrane Database of Systematic Reviews 2005 to August 2015, Database of Abstracts of Reviews of Effects 2nd Quarter 2015, Health Technology Assessment 3rd Quarter 2015, NHS Economic Evaluation Database 2nd Quarter 2015. A detailed search strategy was developed to identify all relevant studies from the published literature; details on the full search strategies used are provided in the online supporting information (see Additional file 2: Tables S2–S4).

The following additional sources were hand-searched: reference lists of included studies; relevant systematic reviews and meta-analyses identified in the electronic database searches and initially excluded; conference proceedings (American Society for Reproductive Medicine [ASRM]; European Society for Human Reproduction and Embryology [ESHRE]; International Society For Pharmaco-economics and Outcomes Research [ISPOR]; International Society for Quality of Life Research [ISOQOL]); clinical trial registries (ClinicalTrials.gov on 28th September 2015); PRO databases (Patient-Reported Outcome and Quality of Life Instruments Database [PROQOLID]; Patient-Reported Outcome Labels Database [PROLabels] on 24th September 2015).

Titles and abstracts of the studies identified in the database searches were screened by one experienced analyst (NA), applying the eligibility criteria for study inclusion (provided in the online supporting information, Table S1), and non-relevant studies were excluded (first pass). Studies that could not be excluded on the basis of title and abstract were retrieved for full publication review (second pass) by all members of the study team. Studies, abstracts, clinical trials and PRO measures identified from hand-searches were assessed applying the eligibility criteria, and the relevant studies were included in the review.

Detailed review of identified patient-reported outcome measures

The PRO measures reported in the included studies were extracted to form a list. The identified PRO measures were then shortlisted according to the selection criteria outlined in Table 1, to identify the measures deemed most appropriate for use in infertility interventional studies.
Table 1

Criteria for the selection of PRO measures for detailed review and psychometric evaluation

Criterion

Include

Exclude

Setting

• Used in an infertility treatment setting

• Used to assess the QoL/psychological health of people living with female infertility but not receiving treatment

Intended population/context of use

• Designed specifically to assess the QoL/treatment satisfaction/psychological health of individuals affected by female infertility

• It is a general QoL/treatment satisfaction/psychological health assessment tool that can be used in multiple disease areas

Treatment type

• It is not treatment-specific

• It is treatment-specific

Previous use in the literature

• Has been used by at least two separate research groupsa

• Used in multiple publications but by a singular research group

Language

• Available in an English-language version

• Not available in an English-language version

Psychometric data

• Psychometric assessment of the PRO conducted, published in the literature, and accessible for use

• Psychometric assessment not conducted

• Psychometric assessment conducted but results are not accessible in the literature

PRO patient reported outcome, QoL quality of life

aThe authors of the publications of at least two studies using the PRO do not overlap

These short-listed PRO measures were then reviewed in light of the FDA PRO Guidance for Industry, which summarises best practice for PRO measures used in clinical development [22]. In particular, the selected PRO measures were assessed for content validity and psychometric performance in the intended population of use, and practical considerations for use in multi-national clinical research.

To conduct this evaluation, the development publication and any subsequent publications further assessing the psychometric properties of each PRO measure were retrieved via hand-searching.

Further details on the specific parameters considered for the assessment of the selected PRO measures are provided in the online supporting information (see Additional file 3: Tables S5–S7). In addition, a gap analysis to evaluate the evidence for content and psychometric validity of the selected PRO measures was also conducted, in context of FDA and EMA regulatory requirements [22, 23].

Results

Study selection

The searching strategy (Fig. 1) identified a total of 4,631 citations. Following removal of duplicate citation records, 3,354 publications were screened by title and abstract yielding 246 potentially relevant publications which were screened on the basis of the full publication. Upon review of the full publications, a further 213 publications were excluded yielding 33 relevant publications. A list of excluded studies at second pass, along with the rationale for exclusion, is provided in the online supporting information (see Additional file 4: Table S8). Through hand-searching of additional publications, conference proceedings, clinical trials registries and PRO measure databases, an additional 89 relevant publications were identified. In total, 122 publications (98 full publications, 24 abstracts) reporting data on 115 unique studies were included in the review.
Fig. 1

Literature review – flow diagram for study inclusion

Patient-reported outcome measures selected for detailed review

The process followed to select the PRO measures for detailed review is described in Fig. 2. The 115 unique studies, identified through structured literature search, used a total of 78 unique PRO measures. Of these 78 unique PRO measures, five PRO measures, reported across 23 studies [2448], were found to meet all selection criteria for detailed review and psychometric evaluation (Table 2). A summary of domains and example items included in each PRO measure is presented in Fig. 3. A list of the identified PRO measures excluded from further analysis, along with the reason for their exclusion, is provided in the online supporting information (see Additional file 5: Table S9).
Fig. 2

Flow diagram of PRO measures identified and selected for detailed review

Table 2

PRO measures identified for review and psychometric assessment

PRO Acronym

PRO measure name

Construct Assessed

Studies using PRO, n

Reference

FertiQoL

FertiQoL

Infertility-related quality of life

Treatment satisfaction

12

[24, 27, 30, 3234, 36, 38, 39, 43, 45, 47, 49]

FPI

Fertility Problem Inventory

Infertility-related stress

4

[35, 37, 41, 42]

IFQ

Infertility Questionnaire

Infertility-related emotional impairment

3

[28, 29, 40, 46]

FPS

Fertility Problem Stress

Infertility-related stress

2

[25, 44]

ICQ-I

Illness Cognitions Questionnaire – Adapted for infertility

Infertility-related feelings of helplessness and acceptance

2

[26, 48]

Study results may be reported in more than one publication, resulting in a number of references greater than the number of studies

PRO patient reported outcome

Fig. 3

Overview of PRO domains and example items

Detailed review of the most relevant patient-reported measures for infertility-related QoL

The following five PRO measures of interest were reviewed: Fertility Quality of Life (FertiQoL); Fertility Problem Inventory (FPI); Fertility Problem Stress (FPS); Infertility Questionnaire (IFQ); Illness Cognitions Questionnaire-Adapted for infertility (ICQ-I). The validity of the PRO measures was assessed by considering a variety of characteristics, and therefore it was not possible to define a PRO measure as ‘valid’ or ‘not valid’. However, we were able to weigh the balance according to the findings of our detailed review. Results of statistical tests used to evaluate psychometric properties were interpreted as detailed in Table 3. An overview of findings for content and psychometric validity is presented in Table 4 and Table 5; practical considerations are summarised in Table 6.
Table 3

Interpretation of statistical tests

Property

Statistical test

Value

Interpretation

Internal consistency reliability [65]

Cronbach’s α

>0.70

Acceptable

Test-retest reliability [66]

Intraclass Correlation Coefficient

>0.75

Good reliability

Concurrent/convergent validity [63]

Spearman’s rank correlation coefficient

r ≤ 0.25

r = 0.26–0.49

r = 0.50–0.69

r = 0.70–0.89

r ≥ 0.90

Little if any correlation

Low correlation

Moderate correlation

High correlation

Very high correlation

Table 4

Overview of instrument content validity

Instrument name

Number of items

Acceptable respondent burden

Clarity of instructions

Clarity of item wording

Appropriate and balanced response options

Appropriate recall period

FertiQoL

36

X

FPI

46

X

X

X

FPS

14

X

ICQ-I

12

n/av

X

X

n/av

IFQ

21

X

X

FertiQoL Fertility Quality of Life Questionnaire, FPI Fertility Problem Inventory, FPS Fertility Problem Stress, ICQ-I, Infertility Cognitions Questionnaire adapted for Infertility, IFQ Infertility Questionnaire, n/av not available

Table 5

Overview of psychometric evidence

Instrument name

Validity

Reliability

Responsiveness

Clinically important difference thresholds available

Structural validity

Convergent validity

Concurrent validity

Known groups validity

Internal consistency reliability

Test-retest reliability

FertiQoL

X

X

X

X

FPI

X

X

X

X

FPS

X

X

X

X

X

X

ICQ-I

X

X

X

X

X

X

X

IFQ

X

X

X

X

FPI Fertility Problem Inventory, FPS Fertility Problem Stress, ICC Intra-class Correlation Coefficient, ICQ-I Infertility Cognitions Questionnaire adapted for Infertility, IFQ Infertility Questionnaire

Table 6

Overview of practical considerations

Instrument name

Number of Language versions

Linguistic validation conducted

Length of measure (burden)

Availability of electronic version

FertiQoL

>30

36 items

FPI

>11

X

46 items

X

FPS

2

14 items

X

ICQ-I

3

X

12 items

X

IFQ

2

20 items

X

FertiQoL Fertility Quality of Life Questionnaire, FPI Fertility Problem Inventory, FPS Fertility Problem Stress, ICQ-I Infertility Cognitions Questionnaire adapted for Infertility, IFQ Infertility Questionnaire, ePRO electronic patient-reported outcome

Fertility quality of life

The Fertility Quality of Life (FertiQoL) was developed in 2011 as an international instrument to measure QoL in men and women experiencing fertility problems and includes an additional module for the assessment of treatment satisfaction [15]. Of the infertility-specific PRO measures identified in this literature review, the FertiQoL was found to be the most widely used measure to assess QoL in interventional infertility studies, being used in 12 of the 23 identified studies [24, 27, 30, 3234, 36, 38, 39, 43, 45, 47, 49]. The extensive cognitive debriefing in patients applied in the development of the FertiQoL suggests an adequate face and content validity in terms of number of items included (n = 36), respondent’s burden, clarity of instructions and balance in response options [15]. However, we found a lack of clarity in the recall period, which may prevent a consistent interpretation, and some potential complexity in item wording. In terms of psychometric strength, we found strong evidence for internal consistency reliability, as measured by Cronbach’s alpha values (α values range: 0.72–0.92) [15, 24, 50, 51], and construct validity – especially to support the structure of the conceptual framework of the FertiQoL [15, 51]. The convergent validity of the FertiQoL has been assessed in five studies validating various language versions of the FertiQoL [24, 5053]. In these studies, moderate to low correlations were observed between the FertiQoL Core score and relevant scales of the Medical Outcomes Study Short Form 36 (SF-36) (correlation coefficients range: 0.32-0.53, p < 0.05) and Hospital Anxiety and Depression Scale (HADS) (correlation coefficients range: -0.65 to -0.67, p < 0.01), suggesting that the FertiQoL Core scale measures constructs related to mental health, as expected. Known groups validity has been assessed in four international validation studies; FertiQoL scores were found to differ significantly between patients grouped according to clinically significant treatment outcomes (e.g. no pregnancy, pregnancy and treatment cancellation) [24, 5052]. We found no evidence for test-retest reliability (stability over time), and a lack of established clinically important differences (CIDs).

Fertility problem inventory

The Fertility Problem Inventory (FPI) was developed in 1999 as a specific measure of infertility-related stress in males and females [54] and has been utilised in a number of interventional studies [35, 37, 41, 42]. The FPI was developed through a qualitative literature review to inform the underlying concepts [54]. Limited evidence was found for cognitive testing with patients to fully establish content validity of the FPI. However, while content validity was considered adequate in terms of number of items included (n = 46), conceptual framework [55], respondent’s burden and clarity of instructions, the response scale options may not be balanced due to the lack of a true midpoint of the scale (neutral response). Furthermore, we found some inconsistency in the item wording, which may have an impact on the validity of the data, and a lack of clarity in the recall period which may limit the use of the FPI measure at multiple time points during a clinical trial. With regard to psychometric strength, evidence suggests good internal consistency reliability for the FPI scales (as measured by Cronbach’s alpha values range: 0.77–0.93) [31, 54, 5659], test-retest reliability (correlation coefficient 0.83 following a 30-day interval) [54], and an adequate construct validity, which was assessed by exploring inter-correlations between each domain scale (correlation coefficients range: 0.26–0.66, all p < 0.05) [54]. Furthermore, convergent validity was demonstrated by a significant correlation between the FPI and some theoretically related measures such as the Beck Depression Inventory (correlation coefficients range: 0.29-0.62, all p < 0.05), State Trait Anxiety Index (correlation coefficients: 0.16–0.37, all p < 0.05) and Dyadic Adjustment Scale (marital adjustment, correlation coefficients range: -0.14 to -0.40, all p < 0.01) [54].

Fertility problem stress

The Fertility Problem Stress (FPS) was originally developed in 1991 to assess infertility-related stress [25] and more recently updated to include further input from patients through item-testing [44, 60]. Adequate content validity was observed for the FPS based on a clear response scales and item wording, both validated by patient involvement in the development process, and a low completion burden (14 items included) [44, 60]. Although no conceptual framework is available for the FPS, factor analysis has confirmed its three domain structure [61]. However, the lack of clear recall period may affect reliability of patient responses when administered longitudinally.

With regard to psychometric strength, evidence for internal consistency reliability is available in the form of Cronbach’s alpha values (α values ranges: women, 0.73–0.81; men, 0.72–0.84) which suggest acceptable internal consistency and reliability in measuring a well-defined construct for all FPS scores (38). Test-retest reliability has not been assessed for the FPS; it is therefore unclear whether scores would remain stable over time for patients experiencing no change in QoL, and confirmation that the measure can assess true change in relation to treatment. Convergent, divergent and inter-scale validity and known groups’ analysis have not been assessed for the FPS; however, confirmatory factor analysis has supported the structure of the measure (38). Responsiveness of the FPS has not been published and no CIDs in scores have been established.

Infertility questionnaire

The Infertility Questionnaire (IFQ) was developed in 1985 as a simple method of assessing the emotional impairment that accompanies infertility [62]. Unlike the FertiQoL, the IFQ does not assess treatment satisfaction, and has not been widely used in interventional studies, being used in three [28, 29, 40, 46] of the 115 identified studies. We found no published evidence for qualitative exploration of the IFQ to determine conceptual relevance and understanding. The IFQ was found to be adequate in terms of patient burden (21 items included) and clarity of instructions; however, item wording alternates between negatively and positively framed questions, potentially increasing the otherwise low patient burden [62]. The 4-point Likert response scale is skewed towards positive responses which may potentially create bias and/or ceiling effects. The vague recall period observed for the IFQ may also affect reliability of patient responses. With regard to psychometric strength, an acceptable internal consistency reliability, as measured by Cronbach’s alpha values (range: 0.72-0.83), together with an adequate test-retest reliability indicate that the IFQ is a stable assessment over time [62]. We found no evidence for assessment of structural validity, making it unclear whether the structure of the questionnaire is appropriate, and no evidence for known group validity. However, convergent validity, assessed via comparison between the IFQ and the Symptom Checklist 90 (SCL-90), was shown by a low to moderate correlation between the IFQ and the SCL-90 (correlation coefficient for the total test mean scores: 0.58), suggesting that the IFQ measures constructs related to psychiatric health, as expected [63]. No CIDs have been established for the IFQ.

Illness cognitions questionnaire-adapted for infertility

The Illness Cognitions Questionnaire-adapted for infertility (ICQ-I) was created in 2005 [48] as an adaptation of the ICQ, a generic assessment of cognition related to helplessness and acceptance in individuals with chronic diseases [64]. The ICQ-I was utilised in two interventional studies [26, 48]. As the ICQ-I was originally a generic measure, patients with a variety of chronic diseases were involved in the qualitative exploration to determine conceptual relevance and understanding of this measure [64]. Consequently, there is a lack of established evidence for content validity in an infertility patient population.

No conceptual framework is available for the ICQ, and although factor analysis has confirmed the structure of the measure in patients with rheumatoid arthritis and multiple sclerosis, no analysis has been conducted in an infertility population [64].

Internal consistency reliability was assessed in the initial psychometric validation of the original (non-disease specific) ICQ, and again when first adapted for infertility; Cronbach values suggest each domain is reliably measuring a well-defined construct (α values range: 0.86–089). Test-retest reliability was confirmed in the original version of the ICQ [64], but no test-retest reliability has been assessed in patients with infertility. Construct validity, confirmatory factor analysis and known groups’ analysis were assessed for the original ICQ measure, but not confirmed in an infertility population. Furthermore, responsiveness has not been assessed for the ICQ-I, and no CIDs in scores have been established.

Discussion

The aim of this review was to identify reliable and valid PRO measures to assess changes in QoL or treatment satisfaction in clinical studies with female patients following treatment with novel therapies. Through a structured literature review, followed by a selection process based on specified eligibility criteria, the following five infertility-specific PRO measures were identified and reviewed for content and psychometric strength in light of the FDA PRO Guidance for Industry [22]: Fertility Quality of Life (FertiQoL); Fertility Problem Inventory (FPI); Fertility Problem Stress (FPS); Infertility Questionnaire (IFQ); Illness Cognitions Questionnaire-Adapted for infertility (ICQ-I).

Results from the literature review showed that the FertiQoL is the most widely used disease-specific PRO measure to assess infertility-related QoL in interventional studies [24, 27, 30, 3234, 36, 38, 39, 43, 45, 47, 49]. A critical review of the FertiQoL suggests that there is reasonable evidence for an adequate content validity and reliability, including cognitive testing with patients, as well as acceptable psychometric properties which ensure internal consistency and construct reliability for this PRO measure [15]. Of the five PRO measures reviewed, the FertiQoL is the only one including an additional module for the assessment of treatment satisfaction; this may make the FertiQoL a particularly useful PRO measure for inclusion in clinical studies on infertility treatments, as it would allow the assessment of this specific aspect from a patient perspective.

With regard to the other four PRO measures reviewed, the FPS and the IFQ, followed by the FPI, were found to show overall the strongest evidence for content validity, especially in terms of clarity of instructions and balanced response options. The assessment of content validity for the ICQ-I was limited by the lack of established evidence in an infertility patient population, as this measure was originally designed to be a generic measure for patients with a variety of chronic diseases. A lack of clarity in the recall period was found to be a common issue for all reviewed PRO measures including the FertiQoL; this may lead to inconsistent interpretation of the findings and limit the ability to detect changes over time. Reasonable evidence for psychometric strength was also found for the FPI, FPS, IFQ and ICQ-I in terms of internal consistency reliability and construct validity, although, the evidence for the ICQ-I was based on unrelated patient populations. Test-retest reliability was found to be adequate for three of the four PRO measures (FPI, IFQ, ICQ-I); however, limited evidence was found for responsiveness of the measures to change and no thresholds for interpreting changes scores through were identified. All the reviewed PRO measures are available in more than one language version, with the FertiQoL been translated in 30 languages and the FPI in more than ten languages. In contrast, the remaining three PRO measures are only available in two or three different language versions: English and Danish for the FPS; English and Chinese for the IFQ; Dutch, English and Hebrew for the ICQ-I. However, we found scarce or no evidence for adequacy of linguistic and cultural validation for all the PRO measures, therefore further translations and/or linguistic validation may be beneficial for the use of these PRO measures in multinational clinical trials.

Although the FertiQoL was found to be the most widely used PRO measure to assess QoL in interventional infertility studies, some gaps in the evidence for psychometric strength remain. In particular, we noted a lack of test-retest reliability to ensure that the FertiQoL is a stable assessment over the time. In addition, we observed a lack of established CID thresholds for determining meaningful score changes, which combined with a vague recall period, might limit the interpretability of the findings in a clinical trial setting. A similar gap in evidence for established CIDs was also observed for the other reviewed PRO measures.

Whilst evidence for content and psychometric validity of PRO measures is paramount for use in clinical studies and, indeed, clinical practice, there are also practical considerations which affect the feasibility of PRO use. In particular, for longitudinal research where a PRO is to be completed at multiple time points, patient burden is an important consideration in terms of the PRO (e.g. length and complexity) and the reality of patient experience. Assessment of QoL in a therapeutic area which is impacted by multiple situational and psychosocial factors related to conception, pregnancy, and neo- and post-natal experience is inherently complex and thus selection of PRO measures and interpretation of the results obtained must be considered in context of such factors.

This review was conducted through a structured literature search to identify a comprehensive body of literature; however some limitations to this review need to be acknowledged. Firstly, only articles and PRO measures available in English language were included for review; therefore, it is possible that relevant PROs available in non-English languages only may have not been captured and reviewed. Furthermore, the study inclusion parameters limited the scope of this review to PRO measures which had been previously included in interventional studies. Subsequently, instruments which are early in development and have not yet been included in interventional studies might not have been included in this review. Secondly, the 1st pass of abstract screening was completed by one analyst only; at 2nd pass all members of the study team reviewed the list of included studies. As a consequence, some studies using the identified PROs may not have been identified; however, this limitation was mitigated by extensive hand-searching. Finally, this review was undertaken without a qualitative assessment of patient’s experience, either through a review of existing qualitative literature or via primary research with women affected by infertility. Therefore, it was not possible to fully evaluate the conceptual relevance (and content validity) of the PRO measures reviewed.

Despite these limitations, the main findings of this review are in line with those reported in a recent systematic review (SR) assessing questionnaires used to measure QoL of infertile couples [18]. In this SR, the FertiQoL and the FPI were found to be valid measures for the evaluation of infertility problems and its treatment effects, and infertility-related stress respectively; although more investigations on the validity of both measures for use in different cultures and nations was recommended [18]. In contrast with the findings of this review, the same SR found that the FertiQoL and the FPI are rarely used to measure infertility-related QoL in infertility studies; however, it should be noted that this SR assessed and compared both disease-specific and generic PRO measures, such as the Short Form (36) Health Survey (SF-36) [18].

Conclusions

The FertiQoL and the FPI are potentially useful measures of infertility-related QoL in clinical development of novel therapies; however, gaps in evidence for the PRO measures reviewed still remain. To ensure these PRO measures are valid, reliable assessments of patient QoL over time, further research is required to establish the recall period of the questionnaires, to define CIDs to improve guidance in the interpretation of clinically important changes, and to make multiple language translations available for use in multinational trials.

Abbreviations

ART: 

Assisted reproductive technology

ASRM: 

American society for reproductive medicine

CID: 

Clinically important difference

ESHRE: 

European society for human reproduction and embryology

FertiQoL: 

Fertility quality of life questionnaire

FPI: 

Fertility problem inventory

FPS: 

Fertility problem stress

HADS: 

Hospital anxiety and depression scale

ICQ-I: 

Illness Cognitions Questionnaire - Adapted for Infertility

ICSI: 

Intracytoplasmic sperm injection

IFQ: 

Infertility questionnaire

ISOQOL: 

International society for quality of life research

ISPOR: 

International society for pharmacoeconomics and outcomes research

IVF: 

In-vitro fertilisation

n/av: 

Not available

PRO: 

Patient reported outcome

PROQOLID: 

The Patient-reported outcome and quality of life instruments database

QoL: 

Quality of life

SF-36: 

Short form (36) health survey

SR: 

Systematic review

WHO: 

World health organisation

Declarations

Acknowledgements

The authors thank Sonia Alesso, employee of DRG Abacus, for medical writing support on the manuscript.

Funding

Funding for this work was provided by Ferring Pharmaceuticals A/S. Time spent on medical writing support was also funded by Ferring Pharmaceuticals A/S and provided by DRG Abacus.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Authors’ contributions

Structured literature review design and search strategy: NA and SM; data extraction, analysis and interpretation of data in the PRO review: NA, HK, AT; manuscript drafting: NA; HK, RP. All authors read and approved the final version of the manuscript, including the authorship list.

Competing interests

Ferring Pharmaceuticals A/S has commissioned DRG Abacus to consult on patient-reported outcome and health economic strategies for their forthcoming studies. RP is an employee of Ferring Pharmaceuticals A/S. All other authors are employed by DRG Abacus, a health outcomes agency that consults with various pharmaceutical companies.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
DRG Abacus
(2)
Ferring Pharmaceuticals A/S
(3)
DRG Abacus

References

  1. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, Sullivan E, Vanderpoel S, International Committee for Monitoring Assisted Reproductive T, World Health O. International committee for monitoring assisted reproductive technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril. 2009;92:1520–4.View ArticlePubMedGoogle Scholar
  2. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9:e1001356.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Assisted Reproductive Technologies Review Committee: Report of the independent review of assisted reproductive technologies. 2006. http://www.health.gov.au/internet/main/publishing.nsf/Content/79D96DD80F01073ECA257BF0001C1ABB/$File/artrc_report.pdf. Accessed 29 Apr 2016.
  4. European Society of Human Reproduction and Embryology: ART fact sheet. June 2014. https://www.eshre.eu/Press-Room/Resources.aspx. Accessed 29 Apr 2016.
  5. Chachamovich JR, Chachamovich E, Ezer H, Fleck MP, Knauth D, Passos EP. Investigating quality of life and health-related quality of life in infertility: a systematic review. J Psychosom Obstet Gynaecol. 2010;31:101–10.View ArticlePubMedGoogle Scholar
  6. Domar A, Gordon K, Garcia-Velasco J, La Marca A, Barriere P, Beligotti F. Understanding the perceptions of and emotional barriers to infertility treatment: a survey in four European countries. Hum Reprod. 2012;27:1073–9.View ArticlePubMedGoogle Scholar
  7. Huppelschoten AG, van Dongen AJ, Verhaak CM, Smeenk JM, Kremer JA, Nelen WL. Differences in quality of life and emotional status between infertile women and their partners. Hum Reprod. 2013;28:2168–76.View ArticlePubMedGoogle Scholar
  8. Ramezanzadeh F, Aghssa MM, Abedinia N, Zayeri F, Khanafshar N, Shariat M, Jafarabadi M. A survey of relationship between anxiety, depression and duration of infertility. BMC Womens Health. 2004;4:9.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Tan S, Hahn S, Benson S, Janssen OE, Dietz T, Kimmig R, Hesse-Hussain J, Mann K, Schedlowski M, Arck PC, Elsenbruch S. Psychological implications of infertility in women with polycystic ovary syndrome. Hum Reprod. 2008;23:2064–71.View ArticlePubMedGoogle Scholar
  10. Keramat A, Masoomi SZ, Mousavi SA, Poorolajal J, Shobeiri F, Hazavhei SM. Quality of life and its related factors in infertile couples. J Res Health Sci. 2014;14:57–63.PubMedGoogle Scholar
  11. Rashidi B, Montazeri A, Ramezanzadeh F, Shariat M, Abedinia N, Ashrafi M. Health-related quality of life in infertile couples receiving IVF or ICSI treatment. BMC Health Serv Res. 2008;8:186.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Human Fertilisation and Embryology Authority: Fertility treatment in 2012 - trends and figures. http://www.hfea.gov.uk/docs/FertilityTreatment2012TrendsFigures.PDF. Accessed 29 Apr 2016.
  13. Quant HS, Zapantis A, Nihsen M, Bevilacqua K, Jindal S, Pal L. Reproductive implications of psychological distress for couples undergoing IVF. J Assist Reprod Genet. 2013;30:1451–8.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Luk BH, Loke AY. The impact of infertility on the psychological well-being, marital relationships, sexual relationships, and quality of life of couples: A systematic review. J Sex Marital Ther. 2015;41:610–25.View ArticlePubMedGoogle Scholar
  15. Boivin J, Takefman J, Braverman A. The fertility quality of life (FertiQoL) tool: development and general psychometric properties. Hum Reprod. 2011;26:2084–91.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Montazeri A. Infertility and health related quality of life: Minireview of the literature. J Family Reprod Health. 2007;1:55–8.Google Scholar
  17. The World Health Organisation (WHO): Programme on mental health. WHOQOL. Measuring quality of life. 1997. http://www.who.int/mental_health/media/68.pdf. Accessed 29 Apr 2016.
  18. Mousavi SA, Masoumi SZ, Keramat A, Pooralajal J, Shobeiri F. Assessment of questionnaires measuring quality of life in infertile couples: a systematic review. J Reprod Infertil. 2013;14:110–9.PubMedPubMed CentralGoogle Scholar
  19. Leidy NK, Revicki DA, Geneste B. Recommendations for evaluating the validity of quality of life claims for labeling and promotion. Value Health. 1999;2:113–27.View ArticlePubMedGoogle Scholar
  20. Valderas JM, Ferrer M, Mendivil J, Garin O, Rajmil L, Herdman M, Alonso J, Scientific committee on “Patient-Reported Outcomes” of the IN. Development of EMPRO: a tool for the standardized assessment of patient-reported outcome measures. Value Health. 2008;11:700–8.View ArticlePubMedGoogle Scholar
  21. Wiklund I. Assessment of patient-reported outcomes in clinical trials: the example of health-related quality of life. Fundam Clin Pharmacol. 2004;18:351–63.View ArticlePubMedGoogle Scholar
  22. FDA: Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims. 2009. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM193282.pdf. Accessed 29 Apr 2016.
  23. EMA: Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. 2005. http://www.ispor.org/workpaper/emea-hrql-guidance.pdf. Accessed 29 Apr 2016.
  24. Aarts JW, van Empel IW, Boivin J, Nelen WL, Kremer JA, Verhaak CM. Relationship between quality of life and distress in infertility: a validation study of the Dutch FertiQoL. Hum Reprod. 2011;26:1112–8.View ArticlePubMedGoogle Scholar
  25. Abbey A, Halman LJ, Andrews FM. Psychosocial, treatment, and demographic predictors of the stress associated with infertility. Fertil Steril. 1992;57:122–8.View ArticlePubMedGoogle Scholar
  26. Aisenberg Romano G, Ravid H, Zaig I, Schreiber S, Azem F, Shachar I, Bloch M. The psychological profile and affective response of women diagnosed with unexplained infertility undergoing in vitro fertilization. Arch Womens Ment Health. 2012;15:403–11.View ArticlePubMedGoogle Scholar
  27. Asazawa K: Effects of a partnership support program for couples undergoing fertility treatment. Presented at the 31st Annual meeting of ESHRE, Lisbon, Portugal, 14–17 June 2015. Abstract number P-513. 2015.Google Scholar
  28. Beaurepaire J, Jones M, Thiering P, Saunders D, Tennant C. Psychosocial adjustment to infertility and its treatment: male and female responses at different stages of IVF/ET treatment. J Psychosom Res. 1994;38:229–40.View ArticlePubMedGoogle Scholar
  29. Boivin J, Takefman JE. Stress level across stages of in vitro fertilization in subsequently pregnant and nonpregnant women. Fertil Steril. 1995;64:802–10.View ArticlePubMedGoogle Scholar
  30. Castells-Ayuso P, Berenguer-Labaig C, Sanchez-Martin P. Sanchez-Martin F: [Nurses as a support to improve the quality of life during assisted reproduction]. Enfermeria Clinica. 2015;25:110–6.View ArticlePubMedGoogle Scholar
  31. Donarelli Z, Gullo S, Lo Coco G, Marino A, Scaglione P, Volpes A, Allegra A. Assessing infertility-related stress: the factor structure of the Fertility Problem Inventory in Italian couples undergoing infertility treatment. J Psychosom Obstet Gynaecol. 2015;36:58–65.View ArticlePubMedGoogle Scholar
  32. Evans J, Ebai P, John M, Antonius M. Quality of life during assisted fertility treatment using the FertiQoL assessment tool: A comparison between those who have had previous fertility treatment and those who have not; and an assessment of gender differences. Hum Fertil. 2010;13:6.Google Scholar
  33. Ghaheri A, Maroufi Zadeh S, Omani Samani R, Karimi M: Impact of environment and tolerability of treatment on life satisfaction in infertile women. Presented at the 30th Annual meeting of ESHRE, Munich, Germany, 29 June - 2 July 2014. Abstract number P-355. 2014.Google Scholar
  34. Ghaheri A, Maroufizadeh S, Omani Samani R, Ezabadi Z. Effect of treatment failure on infertile women’s quality of life. Int J Fertil Steril. 2014;8:31–2.Google Scholar
  35. Gibson DM, Myers JE. The effect of social coping resources and growth-fostering relationships on infertility stress in women. Greensboro: University of North Carolina; 2000.Google Scholar
  36. Gosalbez G, Nataloni RE, Aula M, Fenrnandez C, Nunez S, Luque L, Ortiz J, Llacer J, Bernabeu R: Is the quality of life in poor ovarian responders (POR) worse than normal responders? a prospective study using fertiqol. Presented at the 30th Annual meeting of ESHRE, Munich, Germany, 29 June - 2 July 2014. Abstract number O-190. 2014.Google Scholar
  37. Gourounti K, Anagnostopoulos F, Vaslamatzis G. The relation of psychological stress to pregnancy outcome among women undergoing in-vitro fertilization and intracytoplasmic sperm injection. Women Health. 2011;51:321–39.View ArticlePubMedGoogle Scholar
  38. Haemmerli Keller K, Alder G, Faeh M, Rohner S, von Wolff M: Three Natural cycle IVF treatment imposes less psychological stress than one conventional IVF treatment cycle. Presented at the 31st Annual meeting of ESHRE, Lisbon, Portugal, 14–17 June 2015. Abstract number O-082. 2015.Google Scholar
  39. Kayser J, Depenbusch M, von Horn K, Schultze-Mosgau A, Griesinger G: Quality of life assessment in German female infertile patients: a prospective cohort study conducted at a university-affiliated infertility care center. Presented at the 30th Annual meeting of ESHRE, Munich, Germany, 29 June - 2 July 2014. Abstract number P-336. 2014.Google Scholar
  40. Lee TY, Sun GH, Chao SC. The effect of an infertility diagnosis on the distress, marital and sexual satisfaction between husbands and wives in Taiwan. Hum Reprod. 2001;16:1762–7.View ArticlePubMedGoogle Scholar
  41. Moura-Ramos M, Gameiro S, Canavarro MC: Women’s attachment anxiety mediates the negative effect of the need for parenthood on psychological wellbeing: a cross-partner analysis. Presented at the 30th Annual meeting of ESHRE, Munich, Germany, 29 June - 2 July 2014. Abstract number P-344. 2014.Google Scholar
  42. Moura-Ramos M, Gameiro S, Canavarro MC, Soares I, Santos TA. The indirect effect of contextual factors on the emotional distress of infertile couples. Psychol Health. 2012;27:533–49.View ArticlePubMedGoogle Scholar
  43. Moura-Ramos M, Sousa AP, Brito R, Silva R, Almeida-Santos T: Satisfaction with fertility care during assisted reproduction treatments and its impact in men and women quality of life. Presented at the 31st Annual meeting of ESHRE, Lisbon, Portugal, 14–17 June 2015. Abstract number P-517. 2015.Google Scholar
  44. Schneider MG, Forthofer MS. Associations of psychosocial factors with the stress of infertility treatment. Health Soc Work. 2005;30:183–91.View ArticlePubMedGoogle Scholar
  45. Tam MYJ, Chan CHY, Chan THY, Wong QS, Lo IPY: Do cultural beliefs play a role in fertility-related quality of life? A study of Chinese women after unsuccessful first IVF cycle. Presented at the 31st Annual meeting of ESHRE, Lisbon, Portugal, 14–17 June 2015. Abstract number P-416. 2015.Google Scholar
  46. Thiering P, Beaurepaire J, Jones M, Saunders D, Tennant C. Mood state as a predictor of treatment outcome after in vitro fertilization/embryo transfer technology (IVF/ET). J Psychosom Res. 1993;37:481–91.View ArticlePubMedGoogle Scholar
  47. Verhaak CM, Aarts JWM, Boivin J, Kremer JAM, Van Empel IWH. Measuring quality of life in infertility using the FertiQoL questionnaire. Hum Reprod. 2010;25:i16–7.View ArticleGoogle Scholar
  48. Verhaak CM, Smeenk JM, Evers AW, van Minnen A, Kremer JA, Kraaimaat FW. Predicting emotional response to unsuccessful fertility treatment: a prospective study. J Behav Med. 2005;28:181–90.View ArticlePubMedGoogle Scholar
  49. Donarelli Z, Lo Coco G, Salerno L, Volpes A, Gullo A, Allegra A, Verhaak C: Couple relationship quality (CRQ) influences women’s and men’s quality of life during the course of infertility treatment. Presented at the 30th Annual meeting of ESHRE, Munich, Germany, 29 June - 2 July 2014. Abstract number P-345. 2014.Google Scholar
  50. Kahyaoglu Sut H, Balkanli Kaplan P: Quality of life in women with infertility via the FertiQoL and the Hospital Anxiety and Depression Scales. Nurs Health Sci. 2014;7(1):84–89.Google Scholar
  51. Melo C, Gameiro S, Canavarro MC, Boivin J: Does the FertiQoL assess quality of life? Results from the validation of the Portuguese version of the FertiQoL. Human Reproduction 2012;27:268–273.Google Scholar
  52. Heredia M, Tenias JM, Rocio R, Amparo F, Calleja MA, Valenzuela JC. Quality of life and predictive factors in patients undergoing assisted reproduction techniques. Eur J Obstet Gynecol Reprod Biol. 2013;167:176–80.View ArticlePubMedGoogle Scholar
  53. Holter H, Sandin-Bojo AK, Gejervall AL, Wikland M, Wilde-Larsson B, Bergh C. Quality of care in an IVF programme from a patient’s perspective: development of a validated instrument. Hum Reprod. 2014;29:534–47.View ArticlePubMedGoogle Scholar
  54. Newton CR, Sherrard W, Glavac I. The Fertility Problem Inventory: measuring perceived infertility-related stress. Fertil Steril. 1999;72:54–62.View ArticlePubMedGoogle Scholar
  55. Moura-Ramos M, Gameiro S, Canavarro MC, Soares I. Assessing infertility stress: re-examining the factor structure of the Fertility Problem Inventory. Hum Reprod. 2012;27:496–505.View ArticlePubMedGoogle Scholar
  56. Gourounti K, Anagnostopoulos F, Vaslamatzis G. Psychometric properties and factor structure of the Fertility Problem Inventory in a sample of infertile women undergoing fertility treatment. Midwifery. 2011;27:660–7.View ArticlePubMedGoogle Scholar
  57. Gullo S, Donarelli Z, Lo Coco G, Marino A, Volpes A, Sammartano F. The fertility problem inventory (FPI): A validation study of the Italian version. Hum Reprod. 2013;28:i264–i5.Google Scholar
  58. Ju Hee K, Shin HS. Validation of a Korean version of Fertility Problem Inventory. Asian Nurs Res. 2014;8:207–14.View ArticleGoogle Scholar
  59. Peng T, Coates R, Merriman G, Zhao Y, Maycock B. Testing the psychometric properties of Mandarin version of the fertility problem inventory (M-FPI) in an infertile Chinese sample. J Psychosom Obstet Gynaecol. 2011;32:173–81.View ArticlePubMedGoogle Scholar
  60. Schmidt L, Holstein BE, Christensen U, Boivin J. Communication and coping as predictors of fertility problem stress: cohort study of 816 participants who did not achieve a delivery after 12 months of fertility treatment. Hum Reprod. 2005;20:3248–56.View ArticlePubMedGoogle Scholar
  61. Schmidt L. Infertility and assisted reproduction in Denmark. Epidemiology and psychosocial consequences. Dan Med Bull. 2006;53:390–417.PubMedGoogle Scholar
  62. Bernstein J, Potts N, Mattox JH. Assessment of psychological dysfunction associated with infertility. J Obstet Gynecol Neonatal Nurs. 1985;14:63s–6s.View ArticlePubMedGoogle Scholar
  63. Munro B: Statistical Methods for Health Care Research. Philadelphia: Lippincott Williams & Wilkins. 2005.Google Scholar
  64. Evers AW, Kraaimaat FW, van Lankveld W, Jongen PJ, Jacobs JW, Bijlsma JW. Beyond unfavorable thinking: the illness cognition questionnaire for chronic diseases. J Consult Clin Psychol. 2001;69:1026–36.View ArticlePubMedGoogle Scholar
  65. Bland JM, Altman DG. Statistics notes: Cronbach’s alpha. 1997.Google Scholar
  66. Portney LG, Watkins MP: Foundations of Clinical Research: Applications to Practice. Upper Saddle River: Pearson/Prentice Hall. 2009.Google Scholar

Copyright

© The Author(s). 2017

Advertisement