Quality of life and psychosocial and physical well-being among 1,023 women during their first assisted reproductive technology treatment: secondary outcome to a randomized controlled trial comparing gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist protocols

ORIGINAL ARTICLE: MENTAL HEALTH, SEXUALITY, AND ETHICS

Quality of life and psychosocial and physical well-being among 1,023 women during their first assisted reproductive technology treatment: secondary outcome to a randomized controlled trial comparing gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist protocols Mette Toftager, M.D., Ph.D.,a Randi Sylvest, M.Sc.,a Lone Schmidt, M.D., Ph.D., D.M.Sc.,b Jeanette Bogstad, M.D.,a Kristine Løssl, M.D., Ph.D.,a Lisbeth Prætorius, M.D.,a Anne Zedeler, Ph.D.,a Thue Bryndorf, M.D., D.M.Sc.,a and Anja Pinborg, M.D., D.M.Sc.a a

Fertility Clinic Section 455, Department of Obstetrics and Gynecology, Hvidovre University Hospital, Hvidovre, Copenhagen, Denmark; and b Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark

Objective: To compare self-reported quality of life, psychosocial well-being, and physical well-being during assisted reproductive technology (ART) treatment in 1,023 women allocated to either a short GnRH antagonist or long GnRH agonist protocol. Design: Secondary outcome of a prospective phase 4, open-label, randomized controlled trial. Four times during treatment a questionnaire on self-reported physical well-being was completed. Further, a questionnaire on self-reported quality of life and psychosocial well-being was completed at the day of hCG testing. Setting: Fertility clinics at university hospitals. Patient(s): Women referred for their first ART treatment were randomized in a 1:1 ratio and started standardized ART protocols. Intervention(s): Gonadotropin-releasing hormone analogue; 528 women allocated to a short GnRH antagonist protocol and 495 women allocated to a long GnRH agonist protocol. Main Outcome Measure(s): Self-reported quality of life, psychosocial well-being, and physical well-being based on questionnaires developed for women receiving ART treatment. Result(s): Baseline characteristics were similar, and response rates were 79.4% and 74.3% in the GnRH antagonist and GnRH agonist groups, respectively. Self-reported quality of life during ART treatment was rated similar and slightly below normal in both groups. However, women in the GnRH antagonist group felt less emotional (adjusted odds ratio [AOR] 0.69), less limited in their everyday life (AOR 0.74), experienced less unexpected crying (AOR 0.71), and rated quality of sleep better (AOR 1.55). Further, women receiving GnRH agonist treatment felt worse physically.

Received March 6, 2017; revised September 12, 2017; accepted September 18, 2017. M.T. has nothing to disclose. R.S. has nothing to disclose. L.S. has nothing to disclose. J.B. has nothing to disclose. K.L. has nothing to disclose. L.P. has nothing to disclose. A.Z. has nothing to disclose. T.B. has nothing to disclose. A.P. has nothing to disclose. The study was funded by an unrestricted research grant from MSD. The funders had no influence on the data collection, analyses, or conclusions of the study. Reprint requests: Mette Toftager, M.D., Hvidovre Hospital, Department of Obstetrics and Gynecology, Fertility Clinic Section 455, Ketteg ard Alle 30, Hvidovre 2650, Denmark (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2017 0015-0282/$36.00 Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2017.09.020 VOL. - NO. - / - 2017

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ORIGINAL ARTICLE: MENTAL HEALTH, SEXUALITY, AND ETHICS Conclusion(s): Women in a short GnRH antagonist protocol rated psychosocial and physical well-being during first ART treatment better than did women in a long GnRH agonist protocol. However, the one item on self-reported general quality of life was rated similarly. Clinical Trial Registration Number: NCT00756028. (Fertil SterilÒ 2017;-:-–-. Ó2017 by American Society for Reproductive Medicine.) Key Words: GnRH antagonist/GnRH agonist, in vitro fertilization, physical well-being, psychosocial well-being, quality of life Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/ 16110-fertility-and-sterility/posts/20406-23994

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nfertility can be very stressful for both men and women, and it is well documented that assisted reproductive technology (ART) treatment can be straining (1–3). Moreover, the psychological burden for the couple can be a major reason for discontinuing treatment (4). These negative psychological effects of ART treatment may have an adverse effect in health on both future mother and infant (5). Many infertile women worry that tension and stress can lead to lack of natural fertility and lack of success with fertility treatment (6). However, a meta-analysis by Boivin et al. (7) found that anxiety and depressive symptoms caused by fertility problems did not compromise the pregnancy rate during a single treatment cycle. Treatment by ART is complex, and many infertile couples find it mentally burdensome; therefore, the psychological burden and outcome of fertility treatment have been investigated in many studies, and contradicting results have been presented. In a meta-analysis from 2015, the authors found a correlation between stress and pregnancy outcome, showing that psychosocial interventions such as cognitive– behavioural therapy and mind–body interventions may be beneficial for reducing distress and for improving the pregnancy outcome of ART treatment (8). The long GnRH agonist protocol might be more stressful and straining to the woman compared with the short GnRH antagonist protocol owing to the length of treatment and the pituitary down-regulation with postmenopausal levels of E2 before gonadotrophin stimulation, associated with side effects comprising hot flushes, headache, night sweats, muscle pain, and weight gain (9, 10). The GnRH agonists have also been associated with negative mood symptoms, such as depression, fatigue, anhedonia, and anxiety, owing to the medically induced hypogonadism (11, 12). Additionally, several clinical studies have found a considerably higher risk of ovarian hyperstimulation syndrome (OHSS) when the long GnRH agonist treatment was used compared with the short GnRH antagonist treatment (13–18). Women treated with the long agonist protocol are more frequently admitted to hospital, primarily owing to development of severe OHSS, which is characterized by massive ovarian enlargement, ascites, hemoconcentration, pleural effusion, and thromboembolism (13, 17–20). Optimizing ART protocols to increase efficacy and success of treatment has drawn attention since the first days of IVF (21), whereas less focus has been on psychological strain caused by the different ART treatment modalities. The aim of the present study was to compare self-reported quality of life, psychosocial well-being, and physical well-being in women during their first ART treatment, allocated to either a short 2

GnRH antagonist or a long GnRH agonist protocol; outcomes were secondary outcomes of a large randomized controlled trial (RCT). The overall aim of the RCT ‘‘Short versus Long’’ was to compare the two ART protocols—short GnRH antagonist and long GnRH agonist—in an unselected patient population of women referred for their first ART treatment. A total of 1,023 women started standardized ART treatments with FSH stimulation. The primary aim was to compare risk of OHSS between the two groups, which was significantly lower in the GnRH antagonist group (13). A secondary outcome was to compare cumulative live birth rates between the two arms, which was similar (22). In a smaller substudy, extensive generic psychological testing was performed in 83 women, comparing changes in mental distress and the role of neuroticism for levels of mental distress in the two arms (23). This substudy revealed that the median mood variation during the stimulation phase was more pronounced in the short GnRH antagonist protocol, but this association became nonsignificant after applying a Bonferroni-Holm correction. However, the authors found that neuroticism was associated with increased levels of mental distress throughout treatment in both groups (23). If a difference in distress actually exists, this might be concealed by using generic types of questionnaires and by the limited sample size of the substudy. In the present study a fertility-specific questionnaire was developed and applied, which may improve the assessment of quality of life and psychosocial well-being during ART treatment.

MATERIALS AND METHODS Study Design Quality of life, psychosocial well-being, and physical well-being were secondary outcomes in a large phase 4, open-label, dualcenter, randomized controlled trial, with the objective to compare short GnRH antagonist and long GnRH agonist protocols in an unselected population referred for their first ART treatment. Women were randomized from January 2009 to December 2014 in a ratio 1:1. The protocol is described in detail elsewhere (13). The aim of the present study was to compare quality of life and psychosocial and physical well-being between women in the two arms on the basis of self-reported questionnaires.

Participants We approached all women <40 years of age, referred for their first ART treatment at two public fertility clinics at university hospitals in Denmark: Hvidovre Hospital, Copenhagen and VOL. - NO. - / - 2017

Fertility and Sterility® Dronninglund Hospital, Aalborg. Women were randomized to either a short GnRH antagonist or long GnRH agonist protocol in the early follicular phase (cycle day 1–3). The primary exclusion criterion was prior ART treatment; other minor exclusion criteria are described in reference (13).

Treatment Protocols A total of 1,023 women started a standardized ART treatment with recombinant human follitropin-b (rFSH) stimulation, 528 in the antagonist group and 495 in the agonist group. Women allocated to short antagonist treatment received a daily injection with rFSH (Puregon; MSD, Ballerup, Denmark) from cycle day 2 or 3. A GnRH antagonist (Orgalutran [ganirelix], MSD) was administered daily from stimulation day 6 and until final follicular maturation. Women allocated to long agonist treatment started daily nasal administration of a GnRH agonist (Synarela [nafarelin]; Pfizer, Ballerup, Denmark) on day 21 of the preceding cycle. After 14 days of GnRH agonist administration gonadotrophin stimulation was initiated. The GnRH agonist was continued during rFSH stimulation and until final follicular maturation. All women received a fixed dose of rFSH for the first 6 days, either 150 or 225 IU according to age %36 years or age >36 years. Further protocol details are described in reference (13).

Development of Questionnaires To evaluate quality of life and psychosocial and physical well-being during ART treatment two questionnaires for women receiving ART treatment were developed: ‘‘Quality of Life During IVF Treatment’’ and ‘‘Physical Symptoms During IVF Treatment,’’ referred to as ‘‘Quality of Life’’ and ‘‘Physical Symptoms.’’ Both questionnaires were developed in the years 2007–2008 on the basis of two focus group interviews of women receiving either antagonist or agonist treatment, generic questionnaires like the Hopkins Symptom Checklist for physical discomfort and the Hospital Anxiety and Depression Scale, review of the literature, and interviews with fertility experts with extensive experience in clinical IVF (doctors and nurses). The questionnaires were piloted and validated in collaboration with the Center for Patient Experience and Evaluation, Capital Region, Denmark, to ensure a high degree of reliability and to prevent possible systematic misinterpretations. The questionnaire ‘‘Quality of Life’’ was validated in three rounds of a total of 15 individual cognitive interviews, and the questionnaire ‘‘Physical Symptoms’’ was validated in seven individual cognitive interviews. Quality of life and psychosocial well-being. The questionnaire ‘‘Quality of Life’’ includes 28 items and covers three dimensions. They are [1] reactions to the treatment (16 items), [2] openness about IVF treatment (4 items), and [3] relationship to partner (8 items). It assesses current thoughts and feelings related to fertility treatment. The general quality of life question, ‘‘How would you evaluate your quality of life during the treatment?’’ was answered with a number on a scale from 0 to 10, whereby 0–4 is worse than normal, 5 is normal, and 6–10 is better than normal. Most items regarding psychosocial well-being related to the statement, ‘‘To what extent have VOL. - NO. - / - 2017

you.’’ (i.e., ‘‘To what extent have you been feeling more emotional as a result of your treatment?’’), with a four-point Likert response scale: [1] to a great extent, [2] to some extent, [3] to a lesser extent, and [4] not at all. Other items related to the statement, ‘‘How would you rate/evaluate.’’ (i.e. ‘‘How would you rate the quality of your sleep during treatment?), with a three-point response scale: [1] worse, [2] normal, and [3] better. In addition to the 28 items in the questionnaire, two background questions regarding duration of infertility were added. Twenty-one items from the questionnaire ‘‘Quality of Life’’ were categorized into five domains in accordance with the later-developed questionnaire FertiQoL (24). The domains covered [1] general quality of life, [2] emotional distress, [3] mind/body, [4] relational strain, and [5] mental strain. No group analyses were performed to show that the specific items belong to specific domains, owing to high similarity between the items in our questionnaire and FertiQoL. The quality of life questionnaire was handed out on the day of pregnancy test 13–15 days after ET (visit 3), and women had to complete the questionnaire before the result of the pregnancy test was known. If the ET was cancelled, the questionnaire was completed 3 days after the cancellation (visit 2). Physical well-being questionnaire. The questionnaire ‘‘Physical Symptoms’’ covered self-reported symptoms related to OHSS and other side effects associated with ART treatment and the prescribed IVF medication. The measurements consist of evaluation of the subjective symptoms during ART treatment. To evaluate each symptom, the first part of each question had a binary answering category, either yes or no (i.e., ‘‘Do you have stomach pain?). If yes, the subject was asked to grade the symptom on a three-point scale (i.e., ‘‘How would you describe your stomach pain?’’ [1] ‘‘Mild pain,’’ [2] ‘‘Moderate pain,’’ or [3] ‘‘Severe pain’’). The patients completed the questionnaire ‘‘Physical Symptoms’’ four times during ART treatment; at baseline (visit 0), at the day of oocyte retrieval (visit 1), 3 days after ET (visit 2), and at the day of the pregnancy test 13–15 days after ET (visit 3), during which the questionnaire ‘‘Quality of Life’’ was completed. In accordance with the FertiQoL questionnaire, a single item on physical well-being at visit 3 represents the sixth domain, physical strain. To assess physical well-being during ART treatment we focused on self-reported physical health at three visits; visit 0 at baseline; visit 2, at which early OHSS is peaking; and visit 3, at which late OHSS is peaking.

Sample Size Calculation and Randomization The sample size calculation was based on the primary endpoint severe OHSS and is described in detail in reference (13). For the outcome general quality of life on a scale from 0 to 10, a number of simulated data sets with varying response distribution were generated to estimate the SD. We used a very conservative SD estimate of 2.5. It would require 390 respondents in each arm with a 0.05 and b 0.80 to find a difference of 0.5 in the single-item score of general quality of life between the groups. With approximately 510 patients in each treatment group, a response rate of 76% would be sufficient to 3

ORIGINAL ARTICLE: MENTAL HEALTH, SEXUALITY, AND ETHICS reach the required number of respondents. Women were randomized at inclusion in a 1:1 ratio using a Web-based concealed randomization code and stratified by age group (%36 years or >36 years), fertilization procedure (IVF or intracytoplasmic sperm injection [ICSI]) and IVF clinic (Hvidovre or Dronninglund) (13).

Statistical Methods In the comparison of quality of life, psychosocial well-being, and physical well-being between the two treatment groups, a total of 1,023 women starting gonadotropin stimulation were included, and intention-to-treat analysis was applied. Van Elteren's extension of the Wilcoxon rank sum test and the Cochran-Mantel-Haenszel test and were used to analyse continuous and categorical variables, respectively, controlling for the stratification variables age group, fertilization procedure, and IVF clinic. The P values correspond to tests for differences between the two groups with a significance level of 5%. Data are presented as mean (SD) or number (percentage) as relevant. Ordinal logistic regression analyses were made for 11 selected items from the two questionnaires covering the six domains. There were three criteria in the selection process: either [1] items should show a significantly different response distribution between the groups, [2] items for which the difference in duration of treatment might have an impact on the response, or [3] items for which previous literature has suggested that one or the other treatment might have an impact on the response. The outcome measures were response variables with three or more ordered categories (i.e., to a great extent, to some extent, to a lesser extent, and not at all). We assessed the associations between responses and the following covariates: [1] treatment group (GnRH antagonist or GnRH agonist), [2] female age at inclusion (<30 years, 30–36 years, or >36 years), [3] male factor as primary cause of infertility (yes or no), [4] previous delivery (yes or no), [5] conceived in first fresh ART treatment with hCG >10 IU/L(yes or no), [6] moderate–severe OHSS (yes or no), and [7] years of infertility before inclusion (<2 years, 2–3 years, or >3 years). Adjustments were made for the seven independent covariates. All endpoints were exploratory, hence no adjustments for multiple testing were applied, and statistical significance should therefore be interpreted with caution. A goodness of fit test has been performed using a deviance c2 test for all the ordinal logistic regression models. Measures of the predictive power were also calculated using Nagelkerke R2 and were found acceptable but are not reported. Data were analysed using the SAS package, version 9.4 (SAS Institute).

Ethics The study was approved by The Danish Scientific Ethics Committee, Capital Region of Denmark, protocol no. H-B-2008109, and approved by Danish Medicines Agency, EudraCT no. 2008-005452-24. The ClinicalTrials.gov identification number is NCT00756028. The study is reported according to CONSORT statements. All women provided written informed consent. 4

RESULTS Of women treated with the antagonist protocol 79.4% (419 of 528) completed all four to five required questionnaires, compared with 74.3% of women (368 of 495) treated with the agonist protocol (P¼ .06). Among women who had an ET the response rate for the questionnaire ‘‘Quality of Life’’ at visit 3 was 91.3% and 88.0% (P¼ .11) for the antagonist and agonist groups, respectively (Fig. 1). For women who did not have an ET the response rates for ‘‘Quality of Life’’ were lower, but the overall response rate was 88.1% in the antagonist group and 83.8% in the agonist group (P¼ .05). Despite these differences in response rates, a similar proportion of women had an ET in their first ART treatment in both treatment groups: 80.9% in the antagonist group and 82.4% in the agonist group (P¼ .52). The response rates for the questionnaire ‘‘Physical Symptoms’’ at visit 0-3 are shown in Figure 1.

Baseline Characteristics Patient baseline characteristics at visit 0 were comparable regarding age, body mass index, and the distribution of primary cause of infertility. Women in the antagonist group had a higher previous pregnancy rate compared with women in the agonist group (35.4% vs. 28.5%, P¼ .02) but a similar previous delivery rate, and the duration of infertility was on average 2 months shorter (2.5 vs. 2.7, P< .01) (Supplemental Table S1, available online). At baseline, self-reported physical health was comparable in the two groups for all items, with the exception of the fraction of women who had vomited within the last 24 hours before inclusion: n ¼ 1 (0.2%) in the antagonist group compared with n ¼ 7 (1.4%) in the agonist group (P¼ .03).

Quality of Life and Psychosocial Well-Being Twenty-one selected items from the questionnaire ‘‘Quality of Life’’ reflecting quality of life and psychosocial wellbeing were arranged in five domains and are listed in Table 1. For the single item ‘‘general quality of life’’ on a scale from 0–10, where 5 is normal, both groups rated their quality of life during treatment slightly below normal. Women in the antagonist group had a mean score of 4.2 (1.3), compared with 4.1 (1.4) in the agonist group (P¼ .25). Of the remaining items we found significantly different response distributions in six items. The differences were found in three domains: emotional distress, mind/body, and mental strain. A higher frequency of women in the agonist group were feeling more emotional (P< .01), more aggressive (P¼ .02), and experienced more unexpected crying (P< .01) than in the antagonist group, but no difference was seen in the self-evaluation of depressive symptoms. More women in the agonist group experienced poorer quality of sleep (P< .01). Finally, a higher frequency of women in the agonist group were in doubt as to whether they took the medication correctly (P< .01) and were in doubt as to whether their discomfort was more severe than expected (P< .01). The results for the full ‘‘Quality of Life’’ questionnaire are listed in Supplemental Table S2. VOL. - NO. - / - 2017

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FIGURE 1

Randomization n=1050

No FSH stimulation ♦ Spontaneous pregnancies: 22 ♦ Cancelled stimulation:5

Started FSH stimulation n=1023

GnRH Antagonist

GnRH Agonist

n=528

n=495

Visit 0, n=528 Total responders: 482 Response rate: 91.3%

Baseline Physical questionnaire

Visit 0, n=495 Total responders: 445 Response rate: 89.9%

No oocyte pick up (n=7)

No embryo transfer (n=94)

No oocyte pick up (n=8) Visit 1,n=521 Total responders: 502 Response rate: 96.4%

1st Physical questionnaire

Embryo transfer n=427

Visit 2, n=101 Total responders: 80 Response rate:79.2%

Visit 2, n=427 Total responders: 403 Response rate: 94.4%

Visit 3, n= 427 Total responders: 392 Response rate: 91.8%

Visit 2, n=101

Visit 3, n= 427

Total responders: 75

Total responders: 390

Response rate: 74.3%

Response rate: 91.3%

Visit 1,n=487 Total responders: 458 Response rate: 94.0%

No embryo transfer (n=79)

Embryo transfer n=408

2nd Physical questionnaire

3rd Physical

Visit 2, n=408 Total responders: 365 Response rate: 89.5%

Visit 2, n=87 Total responders: 61 Response rate:70.1%

questionnaire

Visit 3, n=408 Total responders: 364 Response rate: 89.2%

Quality of life questionnaire

Total responders: 359

Total responders: 56

Response rate: 88.0%

Response rate: 64.4%

Visit 3, n=408

Visit 2, n=87

An overview of all subjects who started gonadotrophin stimulation in their first assisted reproductive technology cycle after randomization to either short gonadotropin-releasing hormone (GnRH) antagonist or long GnRH agonist protocol. The questionnaire on self-reported physical health was completed four times at: baseline (visit 0), at the day of oocyte retrieval (visit 1), 3 days after embryo transfer (visit 2), and the day of the pregnancy test 13-15 days after embryo transfer (visit 3). The quality of life questionnaire was completed at visit 3, but before the human chorionic gonadotropin result was known. If the woman did not have an embryo transfer, the questionnaire was completed at visit 2. Toftager. Quality of life and well-being during ART. Fertil Steril 2017.

The response distribution for 11 selected items reflecting quality of life and psychosocial well-being were analysed in an ordinal logistic regression model with adjustments for VOL. - NO. - / - 2017

seven predictive factors: treatment group, age categories, male factor infertility, previous delivery, conceived in first fresh ART treatment, moderate–severe OHSS, and duration 5

ORIGINAL ARTICLE: MENTAL HEALTH, SEXUALITY, AND ETHICS

TABLE 1 Items from the questionnaire on quality of life arranged in domains corresponding to FertiQol domains for women who started gonadotropin stimulation in either a GnRH antagonist or GnRH agonist protocol. P value

Item General 10)a How would you evaluate your quality of life during the treatment? Emotional 1) To what extent have you had any of the following reactions as a result of your treatment? a)a Feeling more emotional b)a Feeling more aggressive c)a Feeling more depressed d)a Unexpected crying e) Experiencing mood swings Mind/body 2)a How would you rate the quality of your sleep during treatment? 14)a How preoccupied with fertility treatment have you and your partner been? Relational 18)a How has your interest in sex been during treatment? 19) What has your reduced interest in sex caused? 12) To what extent has the fact that fertility treatment was needed affected your partner? 13) How much have you and your partner discussed the treatment at home? 15) To what extent has your partner been supportive during the treatment? 16)a How has the treatment affected your relationship? 17) How would you evaluate the relationship to your partner during treatment? Mental strain 3) To what extent have the following bothered you? a) Getting blood drawn b)a Limiting everyday life due to treatment 4) Have you been worried if your treatment will be successful? 7) To what extent have you been worried that the hormone treatment affects your body? 9) Have you at any point during the treatment been in doubt. a) whether you took your medication correctly? b) whether your discomfort was more than expected?

.25 < .01 .02 .17 < .01 .10 < .01 .60 .15 .94 .20 .56 .73 .42 .43 .75 .09 .07 .12 < .01 < .01

Note: The P values correspond to tests for difference in response distribution between the two treatment groups: GnRH antagonist and GnRH agonist protocol. For categorical variables, Cochran– Mantel–Haenszel test is used. For continuous variables, the test is equivalent to van Elteren's extension of the Wilcoxon rank-sum test. The tests are performed controlling for the stratification variables (clinic, age group, and IVF/ICSI). The x) corresponds to the item number in the questionnaire. a The 10 selected items for the ordinal regression models. For detailed results, see Supplemental Table S1. Toftager. Quality of life and well-being during ART. Fertil Steril 2017.

of infertility. All tested models showed good fit, and the proportional odds assumption was found insignificant at a 5% level of significance, indicating that the data satisfy the proportional odds assumption. In Table 2 the crude and adjusted model for general quality of life is shown. In the assessment of ‘‘general quality of life’’ based on the single item, no difference between treatment protocols in crude or adjusted odds ratios (AORs) were seen (AOR 0.90; 95% confidence interval [CI] 0.70–1.16; P¼ .42). The only covariate increasing the adjusted risk of poor general quality of life was the development of moderate–severe OHSS (AOR 1.87; 95% CI 1.36–2.56; P0.01), whereas unknown conception in current treatment decreased the adjusted risk of poor general quality of life (AOR 0.69; P< .01). The regression models for the remaining 10 items are shown in Supplemental Table S3. Women in the antagonist group had a lower adjusted risk of being emotional during treatment compared with women in agonist treatment (AOR 0.69; 95% CI 0.53–0.88; P0.01); and women 30–36 years of age (AOR 0.54; 95% CI 0.40–0.72; P< .01) and >36 years of age (AOR 0.38; 95% CI 0.25–0.57; P< .01) had a lower adjusted risk of being emotional during treatment. Treatment group had no effect on how aggressive women were feeling during treatment (AOR 0.76; 95% CI 0.58–1.00; P¼ .053). Being >30 years of age reduced the risk and previous delivery increased the adjusted risk of being 6

aggressive (AOR 2.344; 95% CI 1.42–4.17; P< .01). No differences were seen in crude or adjusted risk of negative mood symptoms between the two treatment groups. The only covariate reducing depressive feelings during ART treatment was being >30 years of age (AOR <0.69; P< .01). Women in the antagonist group had a lower adjusted risk of experiencing unexpected crying during treatment compared with women in the agonist treatment (AOR 0.71; 95% CI 0.55–0.92; P¼ .01), as did women >30 years of age (AOR <0.62; P< .01). The adjusted risk of poor quality of sleep during treatment was lower for women in the antagonist group (AOR 0.64; 95% CI 0.48–0.86; P< .01). Development of moderate– severe OHSS significantly increased the adjusted risk of poor quality of sleep during treatment (AOR 1.63; 95% CI 1.14–2.31; P¼ .01). There was no difference between the treatment groups in how preoccupied patients were with being in fertility treatment, but women who conceived in their first fresh cycle had a decreased adjusted risk of being more preoccupied with fertility treatment (AOR 0.61; 95% CI 0.45–0.81; P< .01), and women aged 30–36 years also had a decreased adjusted risk (AOR 0.72; 95% CI 0.52–0.98; P¼ .04). We did not find any difference in interest in sex and weakened relationship during treatment between the two treatment groups; however, being >36 years of age decreased the adjusted risk of being less interested in sex VOL. - NO. - / - 2017

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TABLE 2 Ordinal logistic regression analyses of the item ‘‘general quality of life’’ during ART in 1,023 women who started gonadotropin stimulation in their first ART treatment cycle. Question Decreased general quality of life Treatment protocol Long agonist Short antagonist Age (y) <30 30–36 >36 Male factor No Yes Previous delivery No Yes Conceived in first fresh treatment (hCG R10 IU/L) No Yes Moderate–severe OHSS No Yes Years of infertility <2 2–3 y >3 y

Crude OR (95% CI)

P value

AORa (95% CI)

P value

1 0.87 (0.68–1.12)

.28

1 0.90 (0.70–1.16)

.42

1 1.02 (0.77–1.35) 0.66 (0.45–0.98)

.90 .04

1 1.04 (0.78–1.39) 0.72 (0.48–1.09)

.78 .12

1 0.95 (0.74–1.22)

.69

1 0.89 (0.69–1.15)

.38

1 0.80 (0.48–1.33)

.39

1 0.88 (0.53–1.47)

.62

1 0.73 (0.56–0.94)

.02

1 0.69 (0.53–0.89)

.01

1 1.84 (1.35–2.51)

< .01

1 1.87 (1.36–2.56)

< .01

1 0.99 (0.74–1.33) 0.80 (0.58–1.10)

.96 .16

1 0.96 (0.71–1.28) 0.79 (0.57–1.08)

.76 .14

Note: P values and 95% CIs correspond to tests for difference in an unadjusted and adjusted ordinal logistic regression model. N ¼ 815 observations (79.7%). Goodness of fit, deviance c2 test, P¼1.0. a Adjusted for the seven independent covariates: treatment group (antagonist or agonist), age group, diagnosis group (male factor or not), previous delivery, pregnancy in current fresh ART treatment, moderate–severe OHSS, and years of infertility. Toftager. Quality of life and well-being during ART. Fertil Steril 2017.

(AOR 0.48; 95% CI 0.30–0.76; P< .01), whereas development of moderate–severe OHSS increased the adjusted risk of less interest in sex (AOR 1.59; 95% CI 1.05–12.41; P¼ .03). Male factor infertility also increased the adjusted risk of less interest in sex (AOR 1.37; 95% CI 1.00–1.86; P< .05) and increased the adjusted risk of weakened relationship due to ART treatment (AOR 1.38; 95% CI 1.04–1.83; P¼ .03). Finally, women in antagonist treatment had a lower adjusted risk of being bothered by limitations in everyday life due to ART treatment compared with women in agonist treatment (AOR 0.74; 95% CI 0.58–0.96; P¼ .02).

Physical Well-Being during Treatment A comparison of self-reported physical well-being during ART treatment between the GnRH antagonist and GnRH agonist groups is listed in Table 3. At visit 2, at which early OHSS is peaking, significantly more women in the agonist group felt worse physically (P< .01), felt bloated (P< .01), and experienced worse dyspnea (P¼ .03). At visit 3, at which late OHSS is peaking, we found more women in the agonist group to have stomach pain as the only significant difference between the groups (P< .01). Further, of the known side effects to prescribed ART medications, we found significantly more women in the agonist group who experienced hot flashes (P< .01), headache (P< .01), mamma hypotrophia (P< .01), dizziness (P< .01), insomnia (P< .01), weight gain (P¼ .04), and vaginal dryness (P< .01). In the antagonist group more women experienced breast tenderness (Supplemental Table S4). VOL. - NO. - / - 2017

Finally, in the regression analysis there was no difference in how the two treatment groups felt physically according to a single item on the day of their pregnancy test. Nevertheless, development of moderate–severe OHSS significantly increased the adjusted risk of worse physically well-being (AOR 3.17; 95% CI 2.10–4.78; P< .01) (Supplemental Table S3).

DISCUSSION One of our main findings was that women in the GnRH agonist group showed a tendency toward feeling more emotional, more aggressive, and more limited in their everyday life during treatment, and experiencing more unexpected crying and poorer quality of sleep. Further, more women in agonist treatment reported more side effects, thus worse physical well-being. However, another main finding was that self-reported general quality of life during ART treatment measured by a single item was rated similar in both groups, which was slightly below normal. Development of moderate–severe OHSS increased the adjusted risk of worse general quality of life, worse psychosocial well-being, and worse physical well-being. However, treatment group did not show significance in any of the ordinal logistic regression models. The diverse psychological and physical effects of ART treatment have been investigated previously, but without consideration of treatment protocol (25–29). Featured outcomes regarding mental health and well-being during ART treatment have been distress, stress, depression, anxiety, 7

ORIGINAL ARTICLE: MENTAL HEALTH, SEXUALITY, AND ETHICS

TABLE 3 Physical well-being during ART treatment at the peak of early OHSS (3 days after transfer) and late OHSS (at the pregnancy test day) in women treated with either GnRH antagonist or GnRH agonist treatment. 3 d after transfer Question 1) How do you feel physically?

3) Do you feel bloated? 5) Do you have nausea? 7) Have you thrown up within the last 24 hours? 9) Do you have abdominal pain? 11) Do you have shortness of breath?

Response

Antagonist (n [ 528)

Agonist (n [ 495)

Really good Good Bad Really bad Missing Yes Missing Yes Missing Yes Missing Yes Missing Yes Missing

86 (16.3) 327 (61.9) 66 (12.5) 4 (0.8) 45 (8.5) 304 (57.6) 45 (8.5) 88 (16.7) 45 (8.5) 4 (0.8) 55 (10.4) 228 (43.2) 46 (8.7) 52 (9.8) 48 (9.1)

43 (8.7) 302 (61.0) 78 (15.8) 3 (0.6) 69 (13.9) 308 (62.2) 72 (14.5) 89 (18.0) 71 (14.3) 9 (1.8) 75 (15.2) 221 (44.6) 70 (14.1) 66 (13.3) 72 (14.5)

Pregnancy test day P value < .01

< .01 .31 .11 .16 .03

Antagonist (n [ 427)

Agonist (n [ 408)

56 (13.1) 290 (67.9) 42 (9.8) 4 (0.9) 35 (8.2) 153 (35.8) 39 (9.1) 71 (16.6) 35 (8.2) 4 (0.9) 41 (9.6) 109 (25.5) 35 (8.2) 49 (11.5) 37 (8.7)

54 (13.2) 248 (60.8) 53 (13.0) 8 (2.0) 45 (11.0) 162 (39.7) 44 (10.8) 70 (17.2) 45 (11.0) 7 (1.7) 49 (12.0) 133 (32.6) 44 (10.8) 55 (13.5) 45 (11.0)

P value .17

.13 .60 .26 < .01 .33

Note: Values are number (percentage). All patients who started gonadotropin stimulation answered a questionnaire on physical health 3 days after ET, when early ovarian hyperstimulation (OHSS) peaks, and at the day of the pregnancy test (14 days after ET), when late OHSS peaks. P value corresponds to tests for difference between the two groups using Cochran-Mantel-Haenszel tests. The tests are performed controlling for the stratification variables (IVF clinic, age group, and IVF/ICSI). Results from the six main items are shown, and the follow-up items are left out of this table. Toftager. Quality of life and well-being during ART. Fertil Steril 2017.

negative mood symptoms, and quality of life, among others. However, these outcomes may be interrelated, making them challenging to measure. One study has shown that women with polycystic ovary syndrome report lower fertilityrelated quality of life (FertiQoL) at baseline compared with women with unexplained infertility (P< .01) (29). Women with primary infertility reported higher levels of fertilityspecific distress compared with women with secondary infertility. Particularly, women trying to conceive without prior pregnancies were distressed (30). Further, older women reported higher levels of fertility-specific distress than younger women, which is in contradiction with our findings. Intensive investigations of women's mental health in association with successful reproductive outcome after ART have been performed. One study found an increasing number of negative life events within 12 months before treatment to be associated with reduced chances of pregnancy. The poorer outcome was possibly mediated by fewer retrieved oocytes due to a state of chronic stress (31). Several studies have explored the effect of GnRH agonist administration during ART treatment. A smaller pilot study (n ¼ 29) showed co-treatment with GnRH agonist as part of an ART treatment to be associated with a substantial increase in depression and anxiety, both scored on a Hamilton rating scale (32). In a more recent randomized, placebocontrolled, double-blind intervention study by Henningsson et al. (33), women received GnRH agonist (n ¼ 31) or placebo (n ¼ 30). The authors found that fluctuation in E2 during GnRH agonist treatment triggered depressive symptoms, corresponding to the increased sensitivity to emotional stimuli often experienced by women in menopause. The GnRH agonist treatment was comparable to the GnRH analogue used in a long ART protocol. To capture an overall estimate of quality of life is complicated. To our knowledge no validated fertility-specific 8

questionnaires covering quality of life and psychosocial well-being during ART treatment existed when this study was planned. In the absence of a validated fertility-specific questionnaire, validated generic quality of life questionnaires were used in previous studies (e.g., the WHOQOL [34]). The most commonly used quality of life measure for infertility was developed for women with polycystic ovarian syndrome (35). Other quality of life measures were intended for specific subpopulations (e.g., male infertility or endometriosis) and were therefore not suitable for all women referred for ART (24). Parallel to the development of our quality of life questionnaire, Boivin et al. (24) developed an international tool to measure quality of life in patients facing fertility problems (FertiQoL). The FertiQoL tool has been translated into 42 languages, validated in several studies (36, 37), and applied in many studies (38–41). The FertiQoL tool is aiming to be the gold standard for measuring impact of infertility and its treatment on quality of life. The covariates included in our regression analyses were chosen based a priori on the assumption that increasing age may have a negative impact on quality of life and psychosocial well-being, owing to the poorer prognosis of live birth (42, 43). Nevertheless, our results showed that increasing age had an unexpected opposite effect in the regression models. Women at increasing age showed a tendency toward feeling less emotional, less aggressive, less depressed, less preoccupied with fertility treatment, experiencing less unexpected crying, and less interested in sex. These findings may be due to more balanced treatment expectations among women at increasing age. Hence, these women may be aware of their poorer prognosis and may expect less and therefore cope better and respond as less distressed. Studies have shown that male factor infertility affects the woman less than the man; it is, however, known that male VOL. - NO. - / - 2017

Fertility and Sterility® factor infertility compared with other causes of infertility affects a couple the most, and being infertile is a risk factor for sexual problems (44, 45). Therefore, we wished to explore the effect of male factor infertility on quality of life and psychosocial well-being in our study. Male factor infertility had no significant effect on general quality of life but contributed significantly in the ordinal logistic regression model in two items: ‘‘interest in sex during treatment’’ and ‘‘effect on the relationship.’’ Women for whom the primary diagnosis of infertility was male factor showed a tendency toward being less interested in sex and weakened relationship due to ART treatment. Previous childbirth may increase the quality of life during treatment and may decrease distress during treatment. However, in our model previous delivery did not show an impact on self-reported quality of life, but it did showed a tendency toward more aggressive feelings, which may be a random finding because this parameter was not significant in any of the other regression analyses. If conception occurs in the first fresh ART cycle, women may experience early pregnancy symptoms, such as breast tenderness, fatigue, and nausea, and these symptoms may affect how they respond to the questionnaire; if they feel pregnant at the day of hCG testing, they may give a more positive evaluation of the treatment. However, we sought to avoid this by handing out the questionnaire before the results of the pregnancy test were given. In our regression models, unknown pregnancy in first fresh ART cycle showed a tendency toward better general quality of life. Further, the adjusted risk of being more preoccupied with fertility treatment was reduced. Clinically relevant OHSS was expected to have a negative impact on how women evaluated their quality of life and psychosocial well-being. Our results showed that development of moderate–severe OHSS reduced self-reported general quality of life, increased the adjusted risk of worse sleep, increased the adjusted risk of being less interested in sex, and decreased the adjusted risk of weakened relationship due to ART treatment. Finally, the adjusted risk of poorer well-being was increased. Increasing duration of infertility is correlated with poorer pregnancy outcome (42), which may have a negative impact on quality of life and psychosocial well-being. In the previous literature the association between duration of infertility and emotional adjustment has been suggested to be nonlinear (46). However, the only regression model in which ‘‘duration of infertility’’ had a significant contribution was for the item ‘‘feeling more aggressive.’’ Our results showed that >3 years of infertility increased the adjusted risk of feeling more aggressive. This may be a random finding, but increasing duration of infertility may increase distress and explain why these women feel more aggressive during treatment. On the basis of our previous findings regarding a significant reduction in moderate and severe OHSS in the short GnRH antagonist protocol, together with comparable live birth rates after first fresh ART cycle and similar cumulative live birth rates in the two treatment groups, there is a strong incentive to suggest the short protocol VOL. - NO. - / - 2017

as first-choice treatment. However, we do not find significant difference in the rating of the general quality of life between the two treatment arms. The findings on psychosocial well-being show a tendency toward better psychosocial well-being in the short GnRH antagonist group, but the results should be interpreted with caution. Further, women treated with the long GnRH agonist protocol seem to experience more side effects and rate their self-reported physical well-being worse compared with women treated with the short GnRH antagonist protocol, as documented in previous studies (9, 10). A shorter duration of gonadotropin stimulation combined with the lower total gonadotropin dose observed in the short GnRH antagonist group may have a beneficial effect on a woman's physical well-being (13, 18). Baseline parameters were comparable between the groups, making risk of selection bias less likely, and items were developed and validated especially for women in ART treatment to ensure a more specific assessment. The inclusion criteria were broad, making the results easy to extrapolate. Results are reported according to the CONSORT statements, and statistical analyses were performed on intention to treat–based principles (13, 22). The questionnaire response rates among women who had an ET were higher than expected for a large RCT including 1,023 women, with response rates ranging from 88.0% to 96.4%. However, the questionnaire response rate at visit 2 among women who either did not have oocytes retrieved or did not have an ET were lower and ranged from 64.4% to 79.2%. Selection bias may have occurred with regard to ET, because patients without physical or mental strain may be less likely to return for the final visit. The option of recall bias may exist owing to the repeated questionnaires, and furthermore, patients were not blinded to treatment protocol owing to the obvious difference in administration of medication, though the prospective design is less likely to cause recall bias. In conclusion, general quality of life based on a single item was rated similar in the two groups. However, in the exploratory model, women receiving short GnRH antagonist treatment showed a tendency toward rating their psychosocial well-being and physical well-being during their first ART treatment better than women receiving the long GnRH agonist protocol. We consider that poorer physical and psychosocial well-being are factors that should not be overlooked with regard to patient perceptions of ART treatment and therefore should be part of decision making in patients and doctors. Acknowledgments: The authors thank the participating infertile women; all doctors, study nurses, nurses, and laboratory staff employed at Hvidovre Fertility Clinic and Dronninglund Fertility Clinic; and Piero Torre, Statistician, PCG Clinical Services, Uppsala, Sweden, for the statistical analyses.

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