UvA-DARE (Digital Academic Repository) Towards the ... · AGs before attempting TESE-ICSI and/or after failed TESE-ICSI. What is known already: Couples with NOA who undergo TESE-ICSI

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Towards the responsible clinical implementation of stem cell-based fertilitytreatments

Hendriks, S.

Publication date2017Document VersionOther versionLicenseOther

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Citation for published version (APA):Hendriks, S. (2017). Towards the responsible clinical implementation of stem cell-basedfertility treatments.

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CHAPTER 6 WHY COUPLES WITH NON-OBSTRUCTIVE AZOOSPERMIA (NOA) WOULD USE ARTIFICIAL GAMETES

Hendriks S Hessel M Mochtar MH Meissner A van der Veen F Repping S Dancet EAF

Human Reproduction. 2016;31(8):1738-1748.

14771_Hendriks_BNW.indd 99 12-10-17 11:22

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ABSTRACT

Study question: Would couples diagnosed with non-obstructive azoospermia (NOA) consider two future treatments with artificial gametes (AGs) as alternatives for testicular sperm extraction followed by ICSI (TESE-ICSI)?

Summary answer: Most couples with NOA (89%) would opt for treatment with AGs before attempting TESE-ICSI and/or after failed TESE-ICSI.

What is known already: Couples with NOA who undergo TESE-ICSI have a 25% chance of conceiving a child. Two future treatments that are being developed are ‘ICSI with artificial sperm formed from somatic cells’ (ICSI with AGs) and ‘natural conception after autotransplantation of in vitro proliferated spermatogonial stem cells’ (natural conception with AGs). It is unknown what treatment preferences patients have.

Study design, size, duration: A cross-sectional survey conducted in 2012–2013, addressing all 921 couples diagnosed with NOA and treated with TESE-ICSI in Dutch fertility clinics between 2007 and 2012. The coded questionnaires were sent by mail and followed up with two reminders.

Participants/materials, setting, methods: We developed the questionnaire based on a literature review and previous qualitative interviews, and included treatment preference and the valuation of nine treatment characteristics. We assessed reliability of the questionnaires and calculated mean importance scores (MISs: 0–10) of each treatment characteristic. We assessed which patient and treatment characteristics were associated with a couple's hypothetical treatment preference using binominal regression.

Main results and the role of chance: The vast majority (89%) of the 494 responding couples (response rate: 54%) would potentially opt for AGs as a first and/or a last resort treatment option. More specifically, as a first treatment couples were likely (67%) to prefer natural conception with AGs over TESE-ICSI and less likely to prefer ICSI with AGs over TESE-ICSI (34%). After failed TESE-ICSI, the majority of couples (75%) would want to attempt ICSI with AGs as a last resort option. The most important characteristics of treatment were safety for children (MIS: 8.2), pregnancy rates (MIS: 7.7) and curing infertility (MIS: 6.8). Costs, burden, naturalness and technological sophistication were of about equal importance (MIS: 3.1–4.0). The majority of patients rated conception at home and moral acceptability as not important (MIS: 1.7 and 0.8, respectively), but the importance attributed to these variables did still affect patients' likeliness to opt for AGs.

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Limitations and reasons for caution: Couples with NOA not opting for TESE-ICSI were not included and might have other perspectives. Couples' hypothetical choices for AGs might differ from their actual choices once data on the costs, safety and pregnancy rates become available from these new treatment options.

Wider implications of the findings: The interest of couples with NOA in potential future treatments with AGs encourages further pre-clinical research. Priority setting for research and future decision-making on clinical application of AGs should take all characteristics important to patients into account.


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Chapter 6

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ABSTRACT

Study question: Would couples diagnosed with non-obstructive azoospermia (NOA) consider two future treatments with artificial gametes (AGs) as alternatives for testicular sperm extraction followed by ICSI (TESE-ICSI)?

Summary answer: Most couples with NOA (89%) would opt for treatment with AGs before attempting TESE-ICSI and/or after failed TESE-ICSI.

What is known already: Couples with NOA who undergo TESE-ICSI have a 25% chance of conceiving a child. Two future treatments that are being developed are ‘ICSI with artificial sperm formed from somatic cells’ (ICSI with AGs) and ‘natural conception after autotransplantation of in vitro proliferated spermatogonial stem cells’ (natural conception with AGs). It is unknown what treatment preferences patients have.

Study design, size, duration: A cross-sectional survey conducted in 2012–2013, addressing all 921 couples diagnosed with NOA and treated with TESE-ICSI in Dutch fertility clinics between 2007 and 2012. The coded questionnaires were sent by mail and followed up with two reminders.

Participants/materials, setting, methods: We developed the questionnaire based on a literature review and previous qualitative interviews, and included treatment preference and the valuation of nine treatment characteristics. We assessed reliability of the questionnaires and calculated mean importance scores (MISs: 0–10) of each treatment characteristic. We assessed which patient and treatment characteristics were associated with a couple's hypothetical treatment preference using binominal regression.

Main results and the role of chance: The vast majority (89%) of the 494 responding couples (response rate: 54%) would potentially opt for AGs as a first and/or a last resort treatment option. More specifically, as a first treatment couples were likely (67%) to prefer natural conception with AGs over TESE-ICSI and less likely to prefer ICSI with AGs over TESE-ICSI (34%). After failed TESE-ICSI, the majority of couples (75%) would want to attempt ICSI with AGs as a last resort option. The most important characteristics of treatment were safety for children (MIS: 8.2), pregnancy rates (MIS: 7.7) and curing infertility (MIS: 6.8). Costs, burden, naturalness and technological sophistication were of about equal importance (MIS: 3.1–4.0). The majority of patients rated conception at home and moral acceptability as not important (MIS: 1.7 and 0.8, respectively), but the importance attributed to these variables did still affect patients' likeliness to opt for AGs.


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Limitations and reasons for caution: Couples with NOA not opting for TESE-ICSI were not included and might have other perspectives. Couples' hypothetical choices for AGs might differ from their actual choices once data on the costs, safety and pregnancy rates become available from these new treatment options.

Wider implications of the findings: The interest of couples with NOA in potential future treatments with AGs encourages further pre-clinical research. Priority setting for research and future decision-making on clinical application of AGs should take all characteristics important to patients into account.


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INTRODUCTION The World Health Organization ranked infertility as the fifth leading health condition associated with disability among populations under the age of 60 years301. Of the 9% of heterosexual couples who suffer from infertility1, about half suffer from male subfertility, of which azoospermia is the most severe form302. Currently, couples with non-obstructive azoospermia (NOA) can only attempt to achieve genetic fatherhood with testicular sperm extraction followed by ICSI (TESE-ICSI). This intervention has an aggregate chance of 25% of resulting in a live birth: spermatozoa are successfully retrieved in 50% of men with NOA and the subsequent use of these spermatozoa in one or more ICSI treatments results in a live birth rate of 50%280. In the foreseeable future, treatments with artificial gametes (AGs) might be offered to couples with NOA129. In this context, ‘artificial’ implies that these gametes or their progenitors have been substantially manipulated in vitro prior to their use in clinical treatment, which includes in vitro expansion or differentiation of these cells. Different treatments with AGs are being developed, which can be grouped into AGs that can only be used in conjunction with ICSI (‘ICSI with AGs’) or AGs that allow for subsequent natural conception (‘natural conception with AGs’)129. ICSI with AGs involves, for instance, the reprogramming of a somatic cell into an induced pluripotent stem cell (iPSC), the subsequent differentiation of this iPSC into a sperm cell and using this sperm cell for ICSI (Figure 1). Alternatively, sperm cells might be differentiated in vitro from other progenitor cells, such as embryonic stem cells129. ICSI with AGs has resulted in sperm formation in mice83 and in humans, but this sperm has not yet been used for fertilization75. Natural conception with AGs involves, for instance, retrieving spermatogonial stem cells (SSCs) by testicular biopsy, proliferating the SSCs in vitro, transplanting these proliferated SSCs into the testes after which spermatogenesis is restored and natural conception can be initiated (Figure 1). Natural conception with AGs has led to the birth of fertile offspring in mice56. In humans, SSCs have successfully been proliferated in vitro while maintaining their functionality, as demonstrated by xenotransplantation into mice281,282. The development of AGs is currently stimulating a lively debate among professionals as AGs would extend and push the current biological, social and ethical limits of (assisted) reproduction220. For example, AGs would enable additional groups of patients (men with azoospermia, same-sex couples and post-menopausal women) to conceive a genetically related child. Taking account of whether and why patients would be interested in using AGs while this new reproductive technology is still under development is crucial for assessing the added value of AGs for clinical practice from the patient perspective. To our


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knowledge, this has not been quantified for AGs or any other reproductive technique.

Our preceding explorative qualitative study revealed that patients value ‘naturalness’, ‘curing infertility’ and ‘technological sophistication’128 besides the traditional treatment characteristics of pregnancy rates, safety, costs and burden303.

This study aimed to examine whether couples with NOA would prefer two potential future treatments with AGs over TESE-ICSI and which patient and treatment characteristics explain their treatment preference.

Figure 1. Two potential future treatments with artificial gametes. Treatment option 1. ICSI with AGs. Reproduction with the treatment ‘ICSI with AGs’ involves the following steps: (i) retrieving somatic cells by means of a skin biopsy (ii) reprogramming these somatic cells into induced pluripotent stem cells (iPSCs), (iii) in vitro differentiation of the iPSCs into SSCs (iv) in vitro differentiation of the SSCs into a sperm cells, (v) using these sperm cells for ICSI. Treatment option 2. Natural conception with artificial gametes (AGs). Reproduction with the treatment ‘natural conception with AGs’ involves the following steps: (i) retrieving spermatogonial stem cells (SSCs) from the testes by means of a biopsy, (ii) proliferating the SSCs in vitro, (iii) transplanting these proliferated SSCs back into the testes, (iv) in vivo differentiation of the transplanted SSCs such that the number of spermatozoa in the ejaculate will increase, and (v) encouraging patients to attempt to achieve natural conception.


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INTRODUCTION The World Health Organization ranked infertility as the fifth leading health condition associated with disability among populations under the age of 60 years301. Of the 9% of heterosexual couples who suffer from infertility1, about half suffer from male subfertility, of which azoospermia is the most severe form302. Currently, couples with non-obstructive azoospermia (NOA) can only attempt to achieve genetic fatherhood with testicular sperm extraction followed by ICSI (TESE-ICSI). This intervention has an aggregate chance of 25% of resulting in a live birth: spermatozoa are successfully retrieved in 50% of men with NOA and the subsequent use of these spermatozoa in one or more ICSI treatments results in a live birth rate of 50%280. In the foreseeable future, treatments with artificial gametes (AGs) might be offered to couples with NOA129. In this context, ‘artificial’ implies that these gametes or their progenitors have been substantially manipulated in vitro prior to their use in clinical treatment, which includes in vitro expansion or differentiation of these cells. Different treatments with AGs are being developed, which can be grouped into AGs that can only be used in conjunction with ICSI (‘ICSI with AGs’) or AGs that allow for subsequent natural conception (‘natural conception with AGs’)129. ICSI with AGs involves, for instance, the reprogramming of a somatic cell into an induced pluripotent stem cell (iPSC), the subsequent differentiation of this iPSC into a sperm cell and using this sperm cell for ICSI (Figure 1). Alternatively, sperm cells might be differentiated in vitro from other progenitor cells, such as embryonic stem cells129. ICSI with AGs has resulted in sperm formation in mice83 and in humans, but this sperm has not yet been used for fertilization75. Natural conception with AGs involves, for instance, retrieving spermatogonial stem cells (SSCs) by testicular biopsy, proliferating the SSCs in vitro, transplanting these proliferated SSCs into the testes after which spermatogenesis is restored and natural conception can be initiated (Figure 1). Natural conception with AGs has led to the birth of fertile offspring in mice56. In humans, SSCs have successfully been proliferated in vitro while maintaining their functionality, as demonstrated by xenotransplantation into mice281,282. The development of AGs is currently stimulating a lively debate among professionals as AGs would extend and push the current biological, social and ethical limits of (assisted) reproduction220. For example, AGs would enable additional groups of patients (men with azoospermia, same-sex couples and post-menopausal women) to conceive a genetically related child. Taking account of whether and why patients would be interested in using AGs while this new reproductive technology is still under development is crucial for assessing the added value of AGs for clinical practice from the patient perspective. To our


103

knowledge, this has not been quantified for AGs or any other reproductive technique.

Our preceding explorative qualitative study revealed that patients value ‘naturalness’, ‘curing infertility’ and ‘technological sophistication’128 besides the traditional treatment characteristics of pregnancy rates, safety, costs and burden303.

This study aimed to examine whether couples with NOA would prefer two potential future treatments with AGs over TESE-ICSI and which patient and treatment characteristics explain their treatment preference.

Figure 1. Two potential future treatments with artificial gametes. Treatment option 1. ICSI with AGs. Reproduction with the treatment ‘ICSI with AGs’ involves the following steps: (i) retrieving somatic cells by means of a skin biopsy (ii) reprogramming these somatic cells into induced pluripotent stem cells (iPSCs), (iii) in vitro differentiation of the iPSCs into SSCs (iv) in vitro differentiation of the SSCs into a sperm cells, (v) using these sperm cells for ICSI. Treatment option 2. Natural conception with artificial gametes (AGs). Reproduction with the treatment ‘natural conception with AGs’ involves the following steps: (i) retrieving spermatogonial stem cells (SSCs) from the testes by means of a biopsy, (ii) proliferating the SSCs in vitro, (iii) transplanting these proliferated SSCs back into the testes, (iv) in vivo differentiation of the transplanted SSCs such that the number of spermatozoa in the ejaculate will increase, and (v) encouraging patients to attempt to achieve natural conception.


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MATERIALS AND METHODS Ethical approval The Institutional Review Boards of the only two Dutch clinics allowed to perform TESE (i.e. Amsterdam Academic Medical Center and Radboud University Medical Center) affirmed that this study is not subjected to the Dutch ‘Medical Research Involving Human Subjects Act’ and did not require further review. The questionnaire The questionnaire included three parts and was preceded with patient information, in text and figures, which explained TESE-ICSI, ICSI with AGs and natural conception with AGs. The first part of the questionnaire included demographic and medical questions and questioned the outcome of TESE-ICSI, the current status of pursuing one's wish for a child and patients' perspectives on their choice for TESE-ICSI. The second part questioned the importance attached to all seven treatment characteristics valued by patients according to preparatory qualitative research128. In addition, the expert panel decided to question the importance of ‘moral acceptability’. This treatment characteristic was not important to the small sample of previously questioned patients128, but is often addressed in opinion papers and reviews from professionals220. The importance of the treatment characteristics curing infertility, burden, naturalness, technological sophistication and moral acceptability, was measured per treatment, using questions that described how these characteristics would play out in the different treatments (e.g. ‘how important do you find the advantage of ICSI with AGs that the male prospective parent is not required to have a testicular biopsy?’). Because the pregnancy rates, the risks for the child, and the costs of the two AG treatments are currently unknown, the importance of these treatment characteristics was questioned in a separate section including general questions rather than questions specified per treatment (e.g. ‘how important do you find a treatment's pregnancy rate?’). In total, we used 26 questions to evaluate the 8 treatment characteristics, which had to be rated on a four-point Likert scale (i.e. not important, fairly important, important and of the utmost importance304,305). Which treatment characteristics were categorized as advantages or disadvantages was based on the preceding qualitative study128. At the end of the second part an open-ended question asked for additional (dis)advantages of the three treatments to test the questionnaire's face-validity. In the third and final part, we asked couples to imagine that two types of treatment with AGs would have been offered to them when they were treated for infertility. We then presented couples with three hypothetical choice sets while assuming equal safety, pregnancy rates, costs, waiting time before start of treatment and treatment duration of all three treatments. More specifically, couples were asked to choose their preferred first treatment in two choice sets: (i) TESE-ICSI or natural conception with AGs and (ii) TESE-ICSI or ICSI with AGs. In a final choice set,


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couples were asked whether they would opt for ICSI with AGs as a last resort option when TESE-ICSI or natural conception with AGs had failed. Since both TESE-ICSI and natural conception with AGs require the presence of germ cells, and ICSI with AG merely requires somatic cells, only the latter was offered as the last resort option129. An expert panel of professionals revised the questionnaire. The questionnaire was tested and improved in two pilot rounds among nine couples with NOA until it proved that filling out the questionnaire was feasible for patients. A copy of the questionnaire can be found in Supplementary data. Dissemination of the questionnaire All 921 couples diagnosed with NOA and having opted for TESE-ICSI in a Dutch fertility clinic between January 2007 and July 2012 were contacted, irrespective of whether their TESE and/or ICSI had been successful. Since only two Dutch clinics were allowed to perform TESE-ICSI, we identified the patients through their clinical databases. Coded questionnaires, to be filled out by the couple, were sent by postal mail accompanied by an invitation letter, a refusal form and a pre-stamped return envelope. Non-responders received two reminders by mail. Analysis Treatment preferences were described with proportions. More specifically, we described the percentage of couples that (i) preferred natural conception with AGs over TESE ICSI as a first treatment; (ii) preferred ICSI with AGs over TESE-ICSI as first treatment and (iii) answered ‘yes’ to the question on whether they would opt for ICSI with AGs as a last resort option if no sperm were retrieved during TESE or if natural conception with AGs had failed. In addition, we combined the latter three questions into one composite outcome variable: ‘would you opt for AGs as a first and/or a last resort treatment option’, to approximate the total number of patients interested in AGs. The psychometric characteristics of the treatment characteristics were evaluated. Item analysis identified questions with high non-response rates. As five treatment characteristics were addressed by different questions based on the preceding qualitative research, we checked whether these questions addressed the same construct (i.e. treatment characteristics) according to the gathered quantitative data304,305. Therefore, we relied on principal component analysis (PCA306) and Cronbach's α-coefficients (reliable if >0.70307) and item total correlations (ITC, reliable if >0.30308). If the PCA categorized a question as measuring a different treatment characteristic than we hypothesized, and Cronbach's α-coefficients and ITCs showed the model improved by transferring this question from the hypothesized treatment characteristic to the characteristic identified by the PCA,


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MATERIALS AND METHODS Ethical approval The Institutional Review Boards of the only two Dutch clinics allowed to perform TESE (i.e. Amsterdam Academic Medical Center and Radboud University Medical Center) affirmed that this study is not subjected to the Dutch ‘Medical Research Involving Human Subjects Act’ and did not require further review. The questionnaire The questionnaire included three parts and was preceded with patient information, in text and figures, which explained TESE-ICSI, ICSI with AGs and natural conception with AGs. The first part of the questionnaire included demographic and medical questions and questioned the outcome of TESE-ICSI, the current status of pursuing one's wish for a child and patients' perspectives on their choice for TESE-ICSI. The second part questioned the importance attached to all seven treatment characteristics valued by patients according to preparatory qualitative research128. In addition, the expert panel decided to question the importance of ‘moral acceptability’. This treatment characteristic was not important to the small sample of previously questioned patients128, but is often addressed in opinion papers and reviews from professionals220. The importance of the treatment characteristics curing infertility, burden, naturalness, technological sophistication and moral acceptability, was measured per treatment, using questions that described how these characteristics would play out in the different treatments (e.g. ‘how important do you find the advantage of ICSI with AGs that the male prospective parent is not required to have a testicular biopsy?’). Because the pregnancy rates, the risks for the child, and the costs of the two AG treatments are currently unknown, the importance of these treatment characteristics was questioned in a separate section including general questions rather than questions specified per treatment (e.g. ‘how important do you find a treatment's pregnancy rate?’). In total, we used 26 questions to evaluate the 8 treatment characteristics, which had to be rated on a four-point Likert scale (i.e. not important, fairly important, important and of the utmost importance304,305). Which treatment characteristics were categorized as advantages or disadvantages was based on the preceding qualitative study128. At the end of the second part an open-ended question asked for additional (dis)advantages of the three treatments to test the questionnaire's face-validity. In the third and final part, we asked couples to imagine that two types of treatment with AGs would have been offered to them when they were treated for infertility. We then presented couples with three hypothetical choice sets while assuming equal safety, pregnancy rates, costs, waiting time before start of treatment and treatment duration of all three treatments. More specifically, couples were asked to choose their preferred first treatment in two choice sets: (i) TESE-ICSI or natural conception with AGs and (ii) TESE-ICSI or ICSI with AGs. In a final choice set,


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couples were asked whether they would opt for ICSI with AGs as a last resort option when TESE-ICSI or natural conception with AGs had failed. Since both TESE-ICSI and natural conception with AGs require the presence of germ cells, and ICSI with AG merely requires somatic cells, only the latter was offered as the last resort option129. An expert panel of professionals revised the questionnaire. The questionnaire was tested and improved in two pilot rounds among nine couples with NOA until it proved that filling out the questionnaire was feasible for patients. A copy of the questionnaire can be found in Supplementary data. Dissemination of the questionnaire All 921 couples diagnosed with NOA and having opted for TESE-ICSI in a Dutch fertility clinic between January 2007 and July 2012 were contacted, irrespective of whether their TESE and/or ICSI had been successful. Since only two Dutch clinics were allowed to perform TESE-ICSI, we identified the patients through their clinical databases. Coded questionnaires, to be filled out by the couple, were sent by postal mail accompanied by an invitation letter, a refusal form and a pre-stamped return envelope. Non-responders received two reminders by mail. Analysis Treatment preferences were described with proportions. More specifically, we described the percentage of couples that (i) preferred natural conception with AGs over TESE ICSI as a first treatment; (ii) preferred ICSI with AGs over TESE-ICSI as first treatment and (iii) answered ‘yes’ to the question on whether they would opt for ICSI with AGs as a last resort option if no sperm were retrieved during TESE or if natural conception with AGs had failed. In addition, we combined the latter three questions into one composite outcome variable: ‘would you opt for AGs as a first and/or a last resort treatment option’, to approximate the total number of patients interested in AGs. The psychometric characteristics of the treatment characteristics were evaluated. Item analysis identified questions with high non-response rates. As five treatment characteristics were addressed by different questions based on the preceding qualitative research, we checked whether these questions addressed the same construct (i.e. treatment characteristics) according to the gathered quantitative data304,305. Therefore, we relied on principal component analysis (PCA306) and Cronbach's α-coefficients (reliable if >0.70307) and item total correlations (ITC, reliable if >0.30308). If the PCA categorized a question as measuring a different treatment characteristic than we hypothesized, and Cronbach's α-coefficients and ITCs showed the model improved by transferring this question from the hypothesized treatment characteristic to the characteristic identified by the PCA,


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we moved this question. The face-validity of the treatment characteristics was assessed by content-analysis of the open-ended questions on additional treatment (dis)advantages133,289. The importance of all final treatment characteristics was described with their mean importance scores (MISs304,305). Therefore, the four-point Likert scale for importance was transformed into MISs assuming that this linear model can approach the ordinal scores304,305. Whether characteristics differed significantly in importance was assessed by examining whether their 95% confidence intervals (CIs) overlapped. To provide more insight on characteristics with low MIS, the proportion of couples rating all questions relevant to that characteristic as ‘not important’ was noted. The influence of couples' baseline characteristics and the importance attached to the treatment characteristics on couples' choice to opt for AGs as a first or a last resort treatment was evaluated with univariate and multivariate binominal regressions. Data were entered into and analysed with the Statistical Package for Social Sciences 22.0 (SPSS, Inc., Chicago, IL, USA). A value of P < 0.05 was considered significant. RESULTS Respondents The response rate was 54% (n = 494); an additional 11% returned the refusal form. Demographic characteristics of the responding couples can be found in Table I. Most responding couples were in their mid-30s, had completed higher education, had a Western European ethnic background, did not have children from previous relationships, did not suffer from female subfertility next to their NOA, and had been attempting to conceive for ∼5 years. About a quarter of the couples had achieved pregnancy after TESE-ICSI. For half of the couples TESE did not retrieve sperm so no further treatment was possible. In the remaining couples sperm had been retrieved using TESE; these couples were either still undergoing ICSI, or had stopped treatment after (one or more) unsuccessful attempts at ICSI. The average end of treatment (i.e. treatment failure due to TESE failure or TESE-ICSI failure or treatment success as embryo transfer resulted in the birth of a child) was ∼2 years ago. After failure of TESE-ICSI, most couples had turned to donor sperm treatment. Other couples were not yet ready for next steps after failure of TESE-ICSI, had given up on their wish for a child, or opted for adoption or for foster care. Overall, almost half of couples had achieved (genetic or non-genetic) parenthood


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Table I. Demographic characteristics of the responding couples Proportions (%) Demographic characteristics Age (years, mean ± SD) Male partner

Female partner 37.0 ± 5.8 (n=491) 33.8 ± 4.7 (n=480)

Higher education Male partner Female partner

224/487 (46%) 246/480 (51%)

2nd line immigrants (parents not born in EU)

Male partner Female partner

62/486 (13%) 84/482 (17%)

Having children from previous relationships 14/473 (3%) Self-reported medical characteristics Female subfertility 61/470 (13%) Number of months of shared unfulfilled wish for a child (mean ± SD)

62.6 ± 39.1 (n=347)

Number of months since ending TESE-ICSI treatment (mean ± SD)

27.3 ±17.9 (n=402)

Self-reported treatment outcome No sperm retrieved during TESE Sperm retrieved, in-between ICSI treatments Sperm retrieved, no successful ICSI Full-term pregnancy after TESE-ICSI

265/494 (54%) 55/494 (11%) 61/494 (12%) 113/494 (23%)

Actions taken regarding wish for a child after failure of TESE-ICSI*

Gave up on wish for a child Not ready for next step Started DST Started foster care Started adoption procedure Full-term pregnancy from DST Parents with foster care Parents after adoption

60/296 (20%) 39/296 (13%) 77/296 (26%) 4/296 (1%) 15/296 (5%) 85/296 (29%) 1/296 (0%) 15/296 (5%)

Became (genetic or non-genetic) parent** 214/453 (47%) Couples’ perspective on their choice for TESE-ICSI Opted for TESE-ICSI as they felt there was no alternative 419/488 (85%) Considered discontinuation TESE-ICSI 109/470 (23%) Regret the choice to attempt TESE-ICSI 12/456 (3%) * Couples with the TESE-ICSI outcomes “no sperm retrieved during TESE” and “sperm retrieved, no successful ICSI” were invited to answer this question ** Included couples with “full-term pregnancy after TESE-ICSI”, couples with “full-term pregnancy from DST”, “parents after adoption”, and “parents with foster care”.

when they filled out the questionnaire. Most couples had opted for TESE-ICSI as they considered it their only option. In retrospect couples did not regret attempting


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we moved this question. The face-validity of the treatment characteristics was assessed by content-analysis of the open-ended questions on additional treatment (dis)advantages133,289. The importance of all final treatment characteristics was described with their mean importance scores (MISs304,305). Therefore, the four-point Likert scale for importance was transformed into MISs assuming that this linear model can approach the ordinal scores304,305. Whether characteristics differed significantly in importance was assessed by examining whether their 95% confidence intervals (CIs) overlapped. To provide more insight on characteristics with low MIS, the proportion of couples rating all questions relevant to that characteristic as ‘not important’ was noted. The influence of couples' baseline characteristics and the importance attached to the treatment characteristics on couples' choice to opt for AGs as a first or a last resort treatment was evaluated with univariate and multivariate binominal regressions. Data were entered into and analysed with the Statistical Package for Social Sciences 22.0 (SPSS, Inc., Chicago, IL, USA). A value of P < 0.05 was considered significant. RESULTS Respondents The response rate was 54% (n = 494); an additional 11% returned the refusal form. Demographic characteristics of the responding couples can be found in Table I. Most responding couples were in their mid-30s, had completed higher education, had a Western European ethnic background, did not have children from previous relationships, did not suffer from female subfertility next to their NOA, and had been attempting to conceive for ∼5 years. About a quarter of the couples had achieved pregnancy after TESE-ICSI. For half of the couples TESE did not retrieve sperm so no further treatment was possible. In the remaining couples sperm had been retrieved using TESE; these couples were either still undergoing ICSI, or had stopped treatment after (one or more) unsuccessful attempts at ICSI. The average end of treatment (i.e. treatment failure due to TESE failure or TESE-ICSI failure or treatment success as embryo transfer resulted in the birth of a child) was ∼2 years ago. After failure of TESE-ICSI, most couples had turned to donor sperm treatment. Other couples were not yet ready for next steps after failure of TESE-ICSI, had given up on their wish for a child, or opted for adoption or for foster care. Overall, almost half of couples had achieved (genetic or non-genetic) parenthood


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Table I. Demographic characteristics of the responding couples Proportions (%) Demographic characteristics Age (years, mean ± SD) Male partner

Female partner 37.0 ± 5.8 (n=491) 33.8 ± 4.7 (n=480)

Higher education Male partner Female partner

224/487 (46%) 246/480 (51%)

2nd line immigrants (parents not born in EU)

Male partner Female partner

62/486 (13%) 84/482 (17%)

Having children from previous relationships 14/473 (3%) Self-reported medical characteristics Female subfertility 61/470 (13%) Number of months of shared unfulfilled wish for a child (mean ± SD)

62.6 ± 39.1 (n=347)

Number of months since ending TESE-ICSI treatment (mean ± SD)

27.3 ±17.9 (n=402)

Self-reported treatment outcome No sperm retrieved during TESE Sperm retrieved, in-between ICSI treatments Sperm retrieved, no successful ICSI Full-term pregnancy after TESE-ICSI

265/494 (54%) 55/494 (11%) 61/494 (12%) 113/494 (23%)

Actions taken regarding wish for a child after failure of TESE-ICSI*

Gave up on wish for a child Not ready for next step Started DST Started foster care Started adoption procedure Full-term pregnancy from DST Parents with foster care Parents after adoption

60/296 (20%) 39/296 (13%) 77/296 (26%) 4/296 (1%) 15/296 (5%) 85/296 (29%) 1/296 (0%) 15/296 (5%)

Became (genetic or non-genetic) parent** 214/453 (47%) Couples’ perspective on their choice for TESE-ICSI Opted for TESE-ICSI as they felt there was no alternative 419/488 (85%) Considered discontinuation TESE-ICSI 109/470 (23%) Regret the choice to attempt TESE-ICSI 12/456 (3%) * Couples with the TESE-ICSI outcomes “no sperm retrieved during TESE” and “sperm retrieved, no successful ICSI” were invited to answer this question ** Included couples with “full-term pregnancy after TESE-ICSI”, couples with “full-term pregnancy from DST”, “parents after adoption”, and “parents with foster care”.

when they filled out the questionnaire. Most couples had opted for TESE-ICSI as they considered it their only option. In retrospect couples did not regret attempting


Chapter 6

108

TESE-ICSI, although nearly one out of four had considered treatment discontinuation during TESE-ICSI. Preferred treatments While assuming equal safety, pregnancy rates and costs of all three treatments, 89% of couples opted for AGs as a first and/or a last resort treatment option (Table II). More specifically, as first treatment couples were likely (67%) to prefer natural conception with AGs over TESE-ICSI and less likely to prefer ICSI with AGs over TESE-ICSI (34%), while the majority would opt for ICSI with AGs after failed TESE-ICSI (75%). The reasons for not wanting ICSI with AGs as a last resort option were not wanting ICSI with AGs (52%), preferring alternative options (e.g. donor sperm treatment; 46%), wanting to discontinue the pursuit of parenthood for psychological well-being (36%) and feeling of becoming too old to become parents (29%). Table II. Preferred treatments Preferred treatments Proportions

(%) Couples opting for AGs as a first and/or last resort treatment 437/494 (89%) Couples preferring natural conception with AGs over TESE-ICSI as first treatment

308/459 (67%)

Couples preferring ICSI with AGs over TESE-ICSI as first treatment

157/464 (34%)

Couples opting for ICSI with AGs as a last resort treatment 365/486 (75%) Reasons for not opting for ICSI with AGs as a last resort treatment

Do not want ICSI with AGs Prefer other options (e.g. AID) Want to discontinue the pursuit of parenthood for psychological well-being Feeling of becoming too old to become parents

63/121 (52%) 55/121 (46%) 43/121 (36%) 35/121 (29%)

The reliability and validity of the questioned treatment characteristics Non-response rates per question were low (≤3%). The quantitative data resulted in making one adjustment to the grouping of questions into treatment characteristics based on qualitative research. More specifically, ‘conception at home versus in vitro fertilization’ turned out to be an independent treatment characteristic rather than part of the treatment characteristic naturalness. After making conception at home an independent ninth treatment characteristic, all treatment characteristics were assessed reliably308 (Table III). The nine treatment characteristics were face-valid, as analysis of the answers to the open-ended questions did not result in additional (dis)advantages of treatment.


109

Treatment characteristics Safety for the child was the most important of the nine treatment characteristics (MIS: 8.2; Table III), the pregnancy rate was the second most important treatment characteristic (MIS: 7.7) and curing infertility was the third most important treatment characteristic (MIS: 6.8). The overlapping confidence intervals of the MIS of burden, naturalness, costs and technological sophistication (MIS: 3.1–4.0) showed that these four characteristics were of equal importance. Conception at home was the second least important treatment characteristic (MIS: 1.7) as a majority of couples (53%) rated every question on conception at home as ‘not important’. Moral acceptability was the least important treatment characteristic (MIS: 0.8) as the majority of couples (74%) ranked every question on moral acceptability as ‘not important’. Couple and treatment characteristics associated with treatment preference The univariate analysis showed that the ethnicity of the male partner as well as the importance couples attached to curing infertility, naturalness and moral acceptability were associated with their likeliness to opt for AGs as a first and/or a last resort treatment option (Table IV). More specifically, if couples had a non-Western ethnicity or if they attached more importance to curing infertility, they were more likely to opt for AGs. The more importance couples attached to naturalness and moral acceptability, the less likely they were to opt for AGs. The multivariate analysis showed that the educational level of the female partner, the duration of the unfulfilled wish for a child, and the importance attributed to pregnancy rates, naturalness, conception at home and moral acceptability were associated with couples' likeliness to opt for AGs as a first and/or a last resort treatment option. More specifically, couples were more likely to opt for AGs if the female partner was highly educated, or if the couple attached more importance to pregnancy rates or conception at home. Couples were less likely to opt for AGs if they had had a long-term unfulfilled wish for a child, or if they attached more importance to naturalness or moral acceptability. DISCUSSION The vast majority (89%) of couples would opt for AGs as a first and/or a last resort treatment option. Safety for children, pregnancy rates and curing infertility were rated as most important characteristics of treatment. Costs, burden, naturalness and technological sophistication were of about equal importance. The majority of patients rated conception at home and moral acceptability as not important. However, the importance attributed to these characteristics did still affect patients' likeliness to opt for AGs.


6

Chapter 6

108

TESE-ICSI, although nearly one out of four had considered treatment discontinuation during TESE-ICSI. Preferred treatments While assuming equal safety, pregnancy rates and costs of all three treatments, 89% of couples opted for AGs as a first and/or a last resort treatment option (Table II). More specifically, as first treatment couples were likely (67%) to prefer natural conception with AGs over TESE-ICSI and less likely to prefer ICSI with AGs over TESE-ICSI (34%), while the majority would opt for ICSI with AGs after failed TESE-ICSI (75%). The reasons for not wanting ICSI with AGs as a last resort option were not wanting ICSI with AGs (52%), preferring alternative options (e.g. donor sperm treatment; 46%), wanting to discontinue the pursuit of parenthood for psychological well-being (36%) and feeling of becoming too old to become parents (29%). Table II. Preferred treatments Preferred treatments Proportions

(%) Couples opting for AGs as a first and/or last resort treatment 437/494 (89%) Couples preferring natural conception with AGs over TESE-ICSI as first treatment

308/459 (67%)

Couples preferring ICSI with AGs over TESE-ICSI as first treatment

157/464 (34%)

Couples opting for ICSI with AGs as a last resort treatment 365/486 (75%) Reasons for not opting for ICSI with AGs as a last resort treatment

Do not want ICSI with AGs Prefer other options (e.g. AID) Want to discontinue the pursuit of parenthood for psychological well-being Feeling of becoming too old to become parents

63/121 (52%) 55/121 (46%) 43/121 (36%) 35/121 (29%)

The reliability and validity of the questioned treatment characteristics Non-response rates per question were low (≤3%). The quantitative data resulted in making one adjustment to the grouping of questions into treatment characteristics based on qualitative research. More specifically, ‘conception at home versus in vitro fertilization’ turned out to be an independent treatment characteristic rather than part of the treatment characteristic naturalness. After making conception at home an independent ninth treatment characteristic, all treatment characteristics were assessed reliably308 (Table III). The nine treatment characteristics were face-valid, as analysis of the answers to the open-ended questions did not result in additional (dis)advantages of treatment.


109

Treatment characteristics Safety for the child was the most important of the nine treatment characteristics (MIS: 8.2; Table III), the pregnancy rate was the second most important treatment characteristic (MIS: 7.7) and curing infertility was the third most important treatment characteristic (MIS: 6.8). The overlapping confidence intervals of the MIS of burden, naturalness, costs and technological sophistication (MIS: 3.1–4.0) showed that these four characteristics were of equal importance. Conception at home was the second least important treatment characteristic (MIS: 1.7) as a majority of couples (53%) rated every question on conception at home as ‘not important’. Moral acceptability was the least important treatment characteristic (MIS: 0.8) as the majority of couples (74%) ranked every question on moral acceptability as ‘not important’. Couple and treatment characteristics associated with treatment preference The univariate analysis showed that the ethnicity of the male partner as well as the importance couples attached to curing infertility, naturalness and moral acceptability were associated with their likeliness to opt for AGs as a first and/or a last resort treatment option (Table IV). More specifically, if couples had a non-Western ethnicity or if they attached more importance to curing infertility, they were more likely to opt for AGs. The more importance couples attached to naturalness and moral acceptability, the less likely they were to opt for AGs. The multivariate analysis showed that the educational level of the female partner, the duration of the unfulfilled wish for a child, and the importance attributed to pregnancy rates, naturalness, conception at home and moral acceptability were associated with couples' likeliness to opt for AGs as a first and/or a last resort treatment option. More specifically, couples were more likely to opt for AGs if the female partner was highly educated, or if the couple attached more importance to pregnancy rates or conception at home. Couples were less likely to opt for AGs if they had had a long-term unfulfilled wish for a child, or if they attached more importance to naturalness or moral acceptability. DISCUSSION The vast majority (89%) of couples would opt for AGs as a first and/or a last resort treatment option. Safety for children, pregnancy rates and curing infertility were rated as most important characteristics of treatment. Costs, burden, naturalness and technological sophistication were of about equal importance. The majority of patients rated conception at home and moral acceptability as not important. However, the importance attributed to these characteristics did still affect patients' likeliness to opt for AGs.


Tabl

e III

. Im

port

ance

of c

hara

cter

istic

s of

cur

rent

and

pot

entia

l fut

ure

trea

tmen

t opt

ions

Tr

eatm

ent

char

acte

ristic

M

IS tr

eatm

ent

char

acte

ristic

(C

I 95%

)

Item

s qu

estio

ned*

R

elia

bilit

y of

ch

arac

teris

tic

Cro

nbac

h’s

alph

a R

ange

of

Item

Tot

al

Cor

rela

tions

. Sa

fety

for

the

child

**

8.2

(8.0

-8.4

) R

isks

on

cong

enita

l abn

orm

aliti

es

na

na

Preg

nanc

y ra

tes*

* 7.

7 (7

.4-7

.9)

Pre

gnan

cy ra

tes

na

na

Cur

ing

infe

rtili

ty

6.8

(6.6

-7.0

) ‘I

wou

ld b

e cu

red’

is a

n ad

vant

age

of n

atur

al c

once

ptio

n w

ith

AG

s 0.

7 0.

4-0.

5

‘It p

oten

tially

allo

ws

birth

of m

ultip

le c

hild

ren

with

out e

xtra

tre

atm

ents

’ is

an a

dvan

tage

of n

atur

al c

once

ptio

n w

ith A

Gs

‘The

con

cept

feel

s fit

ting’

is a

n ad

vant

age

of n

atur

al

conc

eptio

n w

ith A

Gs

B

urde

n 4.

0 (3

.8-4

.2)

‘The

fem

ale

pros

pect

ive

pare

nt is

requ

ired

to h

ave

horm

onal

st

imul

atio

n, e

gg c

ell r

etrie

val a

nd e

mbr

yo tr

ansf

er’ i

s a

disa

dvan

tage

of T

ES

E-IC

SI

0.8

0.4-

0.7

‘The

fem

ale

pros

pect

ive

pare

nt is

requ

ired

to h

ave

horm

onal

st

imul

atio

n, e

gg c

ell r

etrie

val a

nd e

mbr

yo tr

ansf

er’ i

s a

disa

dvan

tage

of I

CS

I with

AG

s ‘T

he fe

mal

e pr

ospe

ctiv

e pa

rent

is n

ot re

quire

d to

hav

e ho

rmon

al s

timul

atio

n, e

gg c

ell r

etrie

val a

nd e

mbr

yo tr

ansf

er’ i

s an

adv

anta

ge o

f nat

ural

con

cept

ion

with

AG

s D

urat

ion

treat

men

t

‘The

mal

e pr

ospe

ctiv

e pa

rent

is re

quire

d to

hav

e a

test

icul

ar

biop

sy’ i

s a

disa

dvan

tage

of T

ESE

-ICS

I ‘T

he m

ale

pros

pect

ive

pare

nt is

not

requ

ired

to h

ave

a te

stic

ular

bio

psy’

is a

n ad

vant

age

of IC

SI w

ith A

Gs

‘The

mal

e pr

ospe

ctiv

e pa

rent

is re

quire

d to

hav

e tw

o te

stic

ular

in

terv

entio

ns’ i

s a

disa

dvan

tage

of n

atur

al c

once

ptio

n w

ith

AG

s N

atur

alne

ss

3.9

(3.7

-4.1

) ‘It

doe

s no

t or h

ardl

y re

quire

spe

rm m

anip

ulat

ion’

is a

n ad

vant

age

of T

ES

E-IC

SI

0.8

0.3-

0.7

‘Spe

rm is

retri

eved

dire

ctly

from

the

test

icle

thus

it fe

els

natu

ral a

nd s

afe’

is a

n ad

vant

age

of T

ES

E-IC

SI

‘The

con

cept

feel

s fu

turis

tic a

nd e

erie

’ is

a di

sadv

anta

ge o

f IC

SI w

ith A

Gs

‘It re

quire

s th

e m

anip

ulat

ion

of c

ells

’ is

a di

sadv

anta

ge o

f IC

SI

with

AG

s ‘T

he c

once

pt fe

els

unna

tura

l and

unc

omfo

rtabl

e’ is

a

disa

dvan

tage

of I

CS

I with

AG

s ‘It

requ

ires

SSC

s m

odifi

catio

n to

indu

ce g

row

th’ i

s a

disa

dvan

tage

of n

atur

al c

once

ptio

n w

ith A

Gs

C

osts

**

3.6

(3.3

-3.9

) (P

erso

nal)

cost

s of

trea

tmen

t na

na

Te

chno

logi

cal

soph

istic

atio

n 3.

1 (2

.8-3

.4)

‘Thi

s te

chni

ques

use

s th

e m

ost m

oder

n te

chno

logi

es’ i

s an

ad

vant

age

of IC

SI w

ith A

Gs

na

na

Con

cept

ion

at

hom

e 1.

7 (1

.4-1

.9)

‘My

child

will

have

bee

n co

ncei

ved

in th

e ho

spita

l, w

hich

is n

ot

plea

sant

” as

a di

sadv

anta

ge o

f TE

SE

-ICS

I 0.

8 0.

6-0.

7

‘My

child

will

have

bee

n co

ncei

ved

in th

e ho

spita

l, w

hich

is n

ot

plea

sant

” as

a di

sadv

anta

ge o

f IC

SI w

ith A

Gs


6

Tabl

e III

. Im

port

ance

of c

hara

cter

istic

s of

cur

rent

and

pot

entia

l fut

ure

trea

tmen

t opt

ions

Tr

eatm

ent

char

acte

ristic

M

IS tr

eatm

ent

char

acte

ristic

(C

I 95%

)

Item

s qu

estio

ned*

R

elia

bilit

y of

ch

arac

teris

tic

Cro

nbac

h’s

alph

a R

ange

of

Item

Tot

al

Cor

rela

tions

. Sa

fety

for

the

child

**

8.2

(8.0

-8.4

) R

isks

on

cong

enita

l abn

orm

aliti

es

na

na

Preg

nanc

y ra

tes*

* 7.

7 (7

.4-7

.9)

Pre

gnan

cy ra

tes

na

na

Cur

ing

infe

rtili

ty

6.8

(6.6

-7.0

) ‘I

wou

ld b

e cu

red’

is a

n ad

vant

age

of n

atur

al c

once

ptio

n w

ith

AG

s 0.

7 0.

4-0.

5

‘It p

oten

tially

allo

ws

birth

of m

ultip

le c

hild

ren

with

out e

xtra

tre

atm

ents

’ is

an a

dvan

tage

of n

atur

al c

once

ptio

n w

ith A

Gs

‘The

con

cept

feel

s fit

ting’

is a

n ad

vant

age

of n

atur

al

conc

eptio

n w

ith A

Gs

B

urde

n 4.

0 (3

.8-4

.2)

‘The

fem

ale

pros

pect

ive

pare

nt is

requ

ired

to h

ave

horm

onal

st

imul

atio

n, e

gg c

ell r

etrie

val a

nd e

mbr

yo tr

ansf

er’ i

s a

disa

dvan

tage

of T

ES

E-IC

SI

0.8

0.4-

0.7

‘The

fem

ale

pros

pect

ive

pare

nt is

requ

ired

to h

ave

horm

onal

st

imul

atio

n, e

gg c

ell r

etrie

val a

nd e

mbr

yo tr

ansf

er’ i

s a

disa

dvan

tage

of I

CS

I with

AG

s ‘T

he fe

mal

e pr

ospe

ctiv

e pa

rent

is n

ot re

quire

d to

hav

e ho

rmon

al s

timul

atio

n, e

gg c

ell r

etrie

val a

nd e

mbr

yo tr

ansf

er’ i

s an

adv

anta

ge o

f nat

ural

con

cept

ion

with

AG

s D

urat

ion

treat

men

t

‘The

mal

e pr

ospe

ctiv

e pa

rent

is re

quire

d to

hav

e a

test

icul

ar

biop

sy’ i

s a

disa

dvan

tage

of T

ESE

-ICS

I ‘T

he m

ale

pros

pect

ive

pare

nt is

not

requ

ired

to h

ave

a te

stic

ular

bio

psy’

is a

n ad

vant

age

of IC

SI w

ith A

Gs

‘The

mal

e pr

ospe

ctiv

e pa

rent

is re

quire

d to

hav

e tw

o te

stic

ular

in

terv

entio

ns’ i

s a

disa

dvan

tage

of n

atur

al c

once

ptio

n w

ith

AG

s N

atur

alne

ss

3.9

(3.7

-4.1

) ‘It

doe

s no

t or h

ardl

y re

quire

spe

rm m

anip

ulat

ion’

is a

n ad

vant

age

of T

ES

E-IC

SI

0.8

0.3-

0.7

‘Spe

rm is

retri

eved

dire

ctly

from

the

test

icle

thus

it fe

els

natu

ral a

nd s

afe’

is a

n ad

vant

age

of T

ES

E-IC

SI

‘The

con

cept

feel

s fu

turis

tic a

nd e

erie

’ is

a di

sadv

anta

ge o

f IC

SI w

ith A

Gs

‘It re

quire

s th

e m

anip

ulat

ion

of c

ells

’ is

a di

sadv

anta

ge o

f IC

SI

with

AG

s ‘T

he c

once

pt fe

els

unna

tura

l and

unc

omfo

rtabl

e’ is

a

disa

dvan

tage

of I

CS

I with

AG

s ‘It

requ

ires

SSC

s m

odifi

catio

n to

indu

ce g

row

th’ i

s a

disa

dvan

tage

of n

atur

al c

once

ptio

n w

ith A

Gs

C

osts

**

3.6

(3.3

-3.9

) (P

erso

nal)

cost

s of

trea

tmen

t na

na

Te

chno

logi

cal

soph

istic

atio

n 3.

1 (2

.8-3

.4)

‘Thi

s te

chni

ques

use

s th

e m

ost m

oder

n te

chno

logi

es’ i

s an

ad

vant

age

of IC

SI w

ith A

Gs

na

na

Con

cept

ion

at

hom

e 1.

7 (1

.4-1

.9)

‘My

child

will

have

bee

n co

ncei

ved

in th

e ho

spita

l, w

hich

is n

ot

plea

sant

” as

a di

sadv

anta

ge o

f TE

SE

-ICS

I 0.

8 0.

6-0.

7

‘My

child

will

have

bee

n co

ncei

ved

in th

e ho

spita

l, w

hich

is n

ot

plea

sant

” as

a di

sadv

anta

ge o

f IC

SI w

ith A

Gs


‘Afte

r thi

s tre

atm

ent m

y ch

ild w

ill no

t be

conc

eive

d in

a

hosp

ital’

as a

n ad

vant

age

of n

atur

al c

once

ptio

n w

ith A

Gs

Mor

al

acce

ptab

ility

0.

8 (0

.6-0

.9)

‘Eth

ical

obj

ectio

ns’ i

s a

disa

dvan

tage

of T

ES

E-IC

SI

0.7

0.5-

0.7

‘Eth

ical

obj

ectio

ns’ i

s a

disa

dvan

tage

of I

CS

I with

AG

s ‘E

thic

al o

bjec

tions

’ is

a di

sadv

anta

ge o

f nat

ural

con

cept

ion

with

AG

s *N

on-re

spon

se p

er it

em a

lway

s ≤3

%.

** B

ecau

se th

e pr

egna

ncy

rate

s, th

e ris

ks fo

r the

chi

ld, a

nd th

e co

sts

of th

e tw

o A

G tr

eatm

ents

are

cur

rent

ly u

nkno

wn,

the

impo

rtanc

e of

thes

e tre

atm

ent c

hara

cter

istic

s w

as q

uest

ione

d in

gen

eral

rath

er th

an s

peci

fied

per t

reat

men

t (e.

g. ‘h

ow im

port

ant

do y

ou fi

nd a

trea

tmen

t’s p

regn

ancy

rate

?’).


113

Table IV. Treatment characteristics defining preferred treatments Couples opting for AGs as a first and/or last resort treatment Binomial univariate regression

Binomial multivariate regression

OR 95% CI P-value

OR 95% CI

P-value

Respondents Age male partner

Age female partner

0.98

0.97

0.93-1.03 0.92-1.03

0.359

0.378

0.98

0.97

0.82-1.16 0.76-1.24

0.779

0.792

Higher education male partner Higher education female partner

1.11

1.06

0.63-1.96 0.61-1.85

0.709

0.842

0.32

8.52

0.56-1.85 1.36-53.46

0.204

0.022

2nd line immigrants male partner 2nd line immigrants female partner

2.07

1.34

1.03-4.19 0.68-2.67

0.042

0.402

0.38

1.52

0.01-9.99 0.07-31.14

0.558

0.785

Having children from previous relationships*

1.55 0.20-12.13

0.674 - - -

Female subfertility 0.93 0.40-2.17

0.867 0.66 0.55-7.96

0.746

Number of months of shared unfulfilled wish for a child

1.00 0.98-1.02

0.834 0.65 0.47-0.88

0.006

Number of months since ending TESE-ICSI treatment

0.95 0.86-1.04

0.269 0.99 0.95-1.03

0.557

Became (genetic or non-genetic) parent

1.73 0.97-3.09

0.062 0.77 0.55-1.08

0.127

Opted for TESE-ICSI as they felt there was no alternative

1.20 0.52-2.77

0.669 0.56 0.09-3.65

0.544

Considered discontinuation TESE-ICSI

0.54 0.29-1.00

0.051 0.41 0.08-2.18

0.293

Regret the choice to attempt TESE-ICSI*

1.58 0.34-7.40

0.564 - - -

Importance of treatment characteristics Safety for the child 0.91 0.80-

1.04 0.143 0.75 0.51-

1.11 0.151


6

‘Afte

r thi

s tre

atm

ent m

y ch

ild w

ill no

t be

conc

eive

d in

a

hosp

ital’

as a

n ad

vant

age

of n

atur

al c

once

ptio

n w

ith A

Gs

Mor

al

acce

ptab

ility

0.

8 (0

.6-0

.9)

‘Eth

ical

obj

ectio

ns’ i

s a

disa

dvan

tage

of T

ES

E-IC

SI

0.7

0.5-

0.7

‘Eth

ical

obj

ectio

ns’ i

s a

disa

dvan

tage

of I

CS

I with

AG

s ‘E

thic

al o

bjec

tions

’ is

a di

sadv

anta

ge o

f nat

ural

con

cept

ion

with

AG

s *N

on-re

spon

se p

er it

em a

lway

s ≤3

%.

** B

ecau

se th

e pr

egna

ncy

rate

s, th

e ris

ks fo

r the

chi

ld, a

nd th

e co

sts

of th

e tw

o A

G tr

eatm

ents

are

cur

rent

ly u

nkno

wn,

the

impo

rtanc

e of

thes

e tre

atm

ent c

hara

cter

istic

s w

as q

uest

ione

d in

gen

eral

rath

er th

an s

peci

fied

per t

reat

men

t (e.

g. ‘h

ow im

port

ant

do y

ou fi

nd a

trea

tmen

t’s p

regn

ancy

rate

?’).


113

Table IV. Treatment characteristics defining preferred treatments Couples opting for AGs as a first and/or last resort treatment Binomial univariate regression

Binomial multivariate regression

OR 95% CI P-value

OR 95% CI

P-value

Respondents Age male partner

Age female partner

0.98

0.97

0.93-1.03 0.92-1.03

0.359

0.378

0.98

0.97

0.82-1.16 0.76-1.24

0.779

0.792

Higher education male partner Higher education female partner

1.11

1.06

0.63-1.96 0.61-1.85

0.709

0.842

0.32

8.52

0.56-1.85 1.36-53.46

0.204

0.022

2nd line immigrants male partner 2nd line immigrants female partner

2.07

1.34

1.03-4.19 0.68-2.67

0.042

0.402

0.38

1.52

0.01-9.99 0.07-31.14

0.558

0.785

Having children from previous relationships*

1.55 0.20-12.13

0.674 - - -

Female subfertility 0.93 0.40-2.17

0.867 0.66 0.55-7.96

0.746

Number of months of shared unfulfilled wish for a child

1.00 0.98-1.02

0.834 0.65 0.47-0.88

0.006

Number of months since ending TESE-ICSI treatment

0.95 0.86-1.04

0.269 0.99 0.95-1.03

0.557

Became (genetic or non-genetic) parent

1.73 0.97-3.09

0.062 0.77 0.55-1.08

0.127

Opted for TESE-ICSI as they felt there was no alternative

1.20 0.52-2.77

0.669 0.56 0.09-3.65

0.544

Considered discontinuation TESE-ICSI

0.54 0.29-1.00

0.051 0.41 0.08-2.18

0.293

Regret the choice to attempt TESE-ICSI*

1.58 0.34-7.40

0.564 - - -

Importance of treatment characteristics Safety for the child 0.91 0.80-

1.04 0.143 0.75 0.51-

1.11 0.151


Chapter 6

114

Pregnancy rates 1.04 0.94-1.14

0.478 1.38 1.02-1.86

0.034

Curability 1.15 1.02-1.30

0.028 1.35 0.97-1.87

0.075

Burden 0.94 0.82-1.07

0.322 0.66 0.42-1.04

0.076

Naturalness 0.55 0.47-0.65

6

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114

Pregnancy rates 1.04 0.94-1.14

0.478 1.38 1.02-1.86

0.034

Curability 1.15 1.02-1.30

0.028 1.35 0.97-1.87

0.075

Burden 0.94 0.82-1.07

0.322 0.66 0.42-1.04

0.076

Naturalness 0.55 0.47-0.65

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impact patients' hypothetical treatment choices320-323 and its importance inevitably results from patients having to use savings and/or cut back on spending for fertility treatments324. The importance attached to treatment burden is not surprising as it has been reported to induce drop-out from a treatment which could help fulfil the strong wish for a child300. This is the first study quantifying the importance of the treatment characteristics naturalness and technological sophistication, which were identified by qualitative research and represent different sides of the same coin128. The importance of naturalness and technological sophistication, corresponds with, respectively, the general populations' reservations against stem cell technology because it interferes with nature and their appreciation of advanced medical technology299,325,326. IVF probably rarely induced reflections on these two treatment characteristics because it is considered as ‘hardly a technological intervention’, which merely does the same as nature does, but in another way259. Compared with the general public, (infertile) patients have been shown to be more favourable towards interference with nature327,328. The two treatment characteristics that had not emerged from our preceding qualitative research as an independent characteristic (conception at home) or important characteristic (moral acceptability) only mattered to a minority of patients, but for these patients it affected their likeliness to opt for AGs as first or last resort treatment128. In line with the findings for naturalness, patients seem to attach less importance to moral acceptability of treatments with AG128 compared with the general public, which does have reservations about the moral acceptability of stem cell-based technologies39,246,299,325,329. The difference in perspective on the importance of naturalness and moral acceptability could be due to patients considering their condition as more severe than the general public and being likely to benefit directly themselves from the treatments246,305,325,327,330,331. The limited importance of the mode of conception could be explained by the fact that in vitro conception instead of conception at home could be considered both an advantage and a disadvantage by couples. On the one hand, in vitro conception increases couples' sense of control and limits the pressure on their sex life332 while on the other hand conception at home provides couples with autonomy333. The fact that the importance attached to curing infertility, naturalness, moral acceptability and conception at home was associated with the likeliness to opt for AGs as a first and/or a last resort treatment option according to uni- and/or multivariate analysis is consistent with the differences between AGs and TESE-ICSI. The value attached to curability was associated with opting for AGs, and natural conception with AGs would cure infertility while TESE-ICSI does not. The value attached to naturalness was associated with not opting for AGs and this is in line with the creation of AGs requiring more in vitro manipulation than TESE-ICSI. The value attached to moral acceptability was associated with not opting for AGs,


117

which may correspond to professionals' views that AGs give rise to new ethical concerns220. The value attached to conception at home was associated with opting for AGs, which could be explained by natural conception with AGs being the only treatment option that would allow conception at home. The fact that the value attached to pregnancy rates was associated with opting for AGs cannot be explained by differences in effectiveness between the three treatments described in the questionnaire. Nevertheless, couples highly valuing pregnancy rates might be more likely to opt for ICSI with AGs as a last resort option, even after TESE-ICSI, as this may increase their cumulative pregnancy rates. The value attached to safety for the child and costs was not associated with treatment preference. This means that participants adhered to the instructions to assume that these characteristics would be equal for all options. The fact that the value attached to burden was not associated with treatment preference might be explained by differences in burden between both presented treatments with AGs and by burden being affected differently for men and women. Finally, the fact that the importance attached to technological sophistication was not associated with treatment preference could indicate that TESE-ICSI and AGs are both considered sophisticated technologies. Interpreting the associations between couples' characteristics and the likeliness to opt for AGs as a first and/or a last resort treatment is challenging. The fact that second-line immigrants were more likely to opt for AGs pulls attention to the importance of couples' socio-cultural context for their motivations for parenthood and fertility treatments261,334. Couples in which the woman was highly educated were more likely to opt for AGs. This is in line with highly educated individuals being less likely to oppose ART or stem cell-based treatments39,246,327 and with woman having a more decisive role than their partner in fertility treatment decision-making335. A longer duration of the wish for a child was associated with being less likely to opt for AGs. This could not be explained by the age of couples. Being less likely to expect a pregnancy from yet another treatment seems not to be the explanation either as previous research showed that the duration of the wish for child had no impact on the couples' expectations of fertility treatment success336. The association might be explained by having had to endure the psychosocial burden of infertility and fertility treatments for a longer time337 as one-third of couples not wanting ICSI with AGs stated that they ‘wanted to discontinue the pursuit of parenthood for their psychological well-being’. This study inspires future research. First, patients' interest in AGs encourages further pre-clinical research and patients' interest in curing infertility pulls attention to treatments that would restore the ability to conceive naturally. Secondly, it would be interesting to examine with discrete choice experiments how patients and clinicians trade-off the valued treatment characteristics against each other in


6

Chapter 6

116

impact patients' hypothetical treatment choices320-323 and its importance inevitably results from patients having to use savings and/or cut back on spending for fertility treatments324. The importance attached to treatment burden is not surprising as it has been reported to induce drop-out from a treatment which could help fulfil the strong wish for a child300. This is the first study quantifying the importance of the treatment characteristics naturalness and technological sophistication, which were identified by qualitative research and represent different sides of the same coin128. The importance of naturalness and technological sophistication, corresponds with, respectively, the general populations' reservations against stem cell technology because it interferes with nature and their appreciation of advanced medical technology299,325,326. IVF probably rarely induced reflections on these two treatment characteristics because it is considered as ‘hardly a technological intervention’, which merely does the same as nature does, but in another way259. Compared with the general public, (infertile) patients have been shown to be more favourable towards interference with nature327,328. The two treatment characteristics that had not emerged from our preceding qualitative research as an independent characteristic (conception at home) or important characteristic (moral acceptability) only mattered to a minority of patients, but for these patients it affected their likeliness to opt for AGs as first or last resort treatment128. In line with the findings for naturalness, patients seem to attach less importance to moral acceptability of treatments with AG128 compared with the general public, which does have reservations about the moral acceptability of stem cell-based technologies39,246,299,325,329. The difference in perspective on the importance of naturalness and moral acceptability could be due to patients considering their condition as more severe than the general public and being likely to benefit directly themselves from the treatments246,305,325,327,330,331. The limited importance of the mode of conception could be explained by the fact that in vitro conception instead of conception at home could be considered both an advantage and a disadvantage by couples. On the one hand, in vitro conception increases couples' sense of control and limits the pressure on their sex life332 while on the other hand conception at home provides couples with autonomy333. The fact that the importance attached to curing infertility, naturalness, moral acceptability and conception at home was associated with the likeliness to opt for AGs as a first and/or a last resort treatment option according to uni- and/or multivariate analysis is consistent with the differences between AGs and TESE-ICSI. The value attached to curability was associated with opting for AGs, and natural conception with AGs would cure infertility while TESE-ICSI does not. The value attached to naturalness was associated with not opting for AGs and this is in line with the creation of AGs requiring more in vitro manipulation than TESE-ICSI. The value attached to moral acceptability was associated with not opting for AGs,


117

which may correspond to professionals' views that AGs give rise to new ethical concerns220. The value attached to conception at home was associated with opting for AGs, which could be explained by natural conception with AGs being the only treatment option that would allow conception at home. The fact that the value attached to pregnancy rates was associated with opting for AGs cannot be explained by differences in effectiveness between the three treatments described in the questionnaire. Nevertheless, couples highly valuing pregnancy rates might be more likely to opt for ICSI with AGs as a last resort option, even after TESE-ICSI, as this may increase their cumulative pregnancy rates. The value attached to safety for the child and costs was not associated with treatment preference. This means that participants adhered to the instructions to assume that these characteristics would be equal for all options. The fact that the value attached to burden was not associated with treatment preference might be explained by differences in burden between both presented treatments with AGs and by burden being affected differently for men and women. Finally, the fact that the importance attached to technological sophistication was not associated with treatment preference could indicate that TESE-ICSI and AGs are both considered sophisticated technologies. Interpreting the associations between couples' characteristics and the likeliness to opt for AGs as a first and/or a last resort treatment is challenging. The fact that second-line immigrants were more likely to opt for AGs pulls attention to the importance of couples' socio-cultural context for their motivations for parenthood and fertility treatments261,334. Couples in which the woman was highly educated were more likely to opt for AGs. This is in line with highly educated individuals being less likely to oppose ART or stem cell-based treatments39,246,327 and with woman having a more decisive role than their partner in fertility treatment decision-making335. A longer duration of the wish for a child was associated with being less likely to opt for AGs. This could not be explained by the age of couples. Being less likely to expect a pregnancy from yet another treatment seems not to be the explanation either as previous research showed that the duration of the wish for child had no impact on the couples' expectations of fertility treatment success336. The association might be explained by having had to endure the psychosocial burden of infertility and fertility treatments for a longer time337 as one-third of couples not wanting ICSI with AGs stated that they ‘wanted to discontinue the pursuit of parenthood for their psychological well-being’. This study inspires future research. First, patients' interest in AGs encourages further pre-clinical research and patients' interest in curing infertility pulls attention to treatments that would restore the ability to conceive naturally. Secondly, it would be interesting to examine with discrete choice experiments how patients and clinicians trade-off the valued treatment characteristics against each other in


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treatment choices277,338. Thirdly, once infertility treatments with AGs are tested in humans, all treatment characteristics identified as important to patients should be evaluated instead of only costs, effectiveness and safety as in classical health technology assessments. Finally, involving patients in pre-implementation reflections on other innovative technologies is suggested, as we demonstrated that this generates new treatment characteristics to take into consideration. Clinical applications of AGs should, however, be preceded by extensive pre-clinical research and a well-informed societal and professional debate30,137,220.

119


Documents

UvA-DARE (Digital Academic Repository) Towards the ... · AGs before attempting TESE-ICSI and/or after failed TESE-ICSI. What is known already: Couples with NOA who undergo TESE-ICSI