Patient-Reported Outcomes (PROs) and Patient Experiences in Fertility Preservation: A Systematic Review of the Literature on Adolescents and Young Adults (AYAs) with Cancer.

With better survival rates for patients diagnosed with cancer, more attention has been focused on future risks, like fertility decline due to gonadotoxic treatment. In this regard, the emphasis during counselling regarding possible preservation options is often on the treatment itself, meaning that the medical and emotional needs of patients regarding counselling, treatment, and future fertility are often overlooked. This review focuses on patient-reported outcomes (PROs) and patient experiences regarding fertility preservation (FP)-among adolescents and young adults (AYAs) with cancer. A systematic review of the literature, with a systematic search of online databases, was performed, resulting in 61 selected articles. A quality assessment was performed by a mixed methods appraisal tool (MMAT). Based on this search, three important topics emerged: initiating discussion about the risk of fertility decline, acknowledging the importance of future fertility, and recognizing the need for more verbal and written patient-specific information. In addition, patients value follow-up care and the opportunity to rediscuss FP and their concerns about future fertility and use of stored material. A clear FP healthcare pathway can prevent delays in receiving a referral to a fertility specialist to discuss FP options and initiating FP treatment. This patient-centered approach will optimize FP experiences and help to establish a process to achieve long-term follow up after FP treatment.

Home-based monitoring of ovulation to time frozen embryo transfers in the Netherlands (Antarctica-2): an open-label, nationwide, randomised, non-inferiority trial.

BACKGROUND: The growing field of assisted reproductive techniques, including frozen-thawed embryo transfer (FET), should lead the way to the best sustainable health care without compromising pregnancy chances. Correct timing of FET is crucial to allow implantation of the thawed embryo. Nowadays, timing based on hospital-controlled monitoring of ovulation in the natural cycle of a woman is the preferred strategy because of the assumption of favourable fertility prospects. However, home-based monitoring is a simple method to prevent patient travel and any associated environmental concerns. We compared ongoing pregnancy rates after home-based monitoring versus hospital-controlled monitoring with ovulation triggering. METHODS: This open-label, multicentre, randomised, non-inferiority trial was undertaken in 23 hospitals and clinics in the Netherlands. Women aged between 18 and 44 years with a regular ovulatory menstrual cycle were randomly assigned in a 1:1 ratio via a web-based randomisation program to home-based monitoring or hospital-controlled monitoring. Those who analysed the data were masked to the groups; those collecting the data were not. All endpoints were analysed by intention to treat and per protocol. Non-inferiority was established when the lower limit of the 90% CI exceeded -4%. This study was registered at the Dutch Trial Register (Trial NL6414). FINDINGS: 1464 women were randomly assigned between April 10, 2018, and April 13, 2022, with 732 allocated to home-based monitoring and 732 to hospital-controlled monitoring. Ongoing pregnancy occurred in 152 (20·8%) of 732 in the home-based monitoring group and in 153 (20·9%) of 732 in the hospital-controlled monitoring group (risk ratio [RR] 0·99 [90% CI 0·81 to 1·22]; risk difference [RD] -0·14 [90% CI -3·63 to 3·36]). The per-protocol analysis confirmed non-inferiority (152 [21·0%] of 725 vs 153 [21·0%] of 727; RR 1·00 (90% CI 0·81 to 1·23); RD -0·08 [90% CI -3·60 to 3·44]). INTERPRETATION: Home-based monitoring of ovulation is non-inferior to hospital-controlled monitoring of ovulation to time FET. FUNDING: The Dutch Organisation for Health Research and Development.

Previous caesarean section is associated with lower subsequent in vitro fertilization live birth rates.

This retrospective cohort study examines the association between previous mode of delivery and subsequent live birth rate in women who become pregnant after in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI) after their first delivery. The study included 112 women with a previous caesarean section and 418 women with a previous vaginal delivery, and a total of 1588 embryo transfers between January 2005 and June 2016 (Leiden University Medical Centre, the Netherlands). The mean age was 35 years and mean number of embryos transferred per attempt, 1.18. The study population included a total of 429 pregnancies resulting in 296 live births. The crude odds ratio for a subsequent live birth per embryo transfer was 0.60 (CI; 0.44 to 0.83, p = 0.002) in women with a previous caesarean section compared to women with a previous vaginal delivery. After adjustment for age, fresh/frozen-thawed embryo transfer and quality of the embryo, the odds ratio was 0.64 (CI; 0.46 to 0.89, p = 0.01). It was concluded that in subfertile women trying to achieve a subsequent pregnancy with IVF or ICSI, a history of caesarean section was associated with a reduced live birth rate per embryo transfer compared to women with a history of one previous vaginal delivery.

Lifestyle intervention prior to IVF does not improve embryo utilization rate and cumulative live birth rate in women with obesity: a nested cohort study.

STUDY QUESTION: Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity? SUMMARY ANSWER: A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved. WHAT IS KNOWN ALREADY: A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos. STUDY DESIGN SIZE DURATION: This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285). PARTICIPANTS/MATERIALS SETTING METHODS: Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total, 137 participants (n = 58 in the intervention group and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the Z-score for singleton neonatal birthweight and compared these outcomes between the two groups. MAIN RESULTS AND THE ROLE OF CHANCE: The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m2 in the intervention group, and 34.9 ± 2.9 kg/m2 in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg vs the control group: -3.14, 95% CI: -5.73 to -0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] vs 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] vs 3.00 [1.00; 5.00]) and the number of cryopreserved embryos (2.00 [1.25; 4.75] vs 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: -8.6% to 14.0%). In the per oocyte/embryo analysis, in total, 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group, EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted odds ratio [OR]: 1.36, 95% CI: 0.94-1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% vs 22.2%, adjusted OR: 1.03, 95% CI: 0.43-2.47). Singleton neonatal birthweight and Z-score were not significantly different between the two groups. LIMITATIONS REASONS FOR CAUTION: This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). A.H. has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. B.W.J.M. has received research funding from Guerbet, Ferring and Merck. F.J.M.B. reports personal fees from membership of the external advisory board for Merck Serono and a research support grant from Merck Serono, outside the submitted work. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530.

First effective mHealth nutrition and lifestyle coaching program for subfertile couples undergoing in vitro fertilization treatment: a single-blinded multicenter randomized controlled trial.

OBJECTIVE: To study compliance and effectiveness of the mHealth nutrition and lifestyle coaching program Smarter Pregnancy in couples undergoing in vitro fertilization (IVF) treatment with or without intracytoplasmic sperm injection (ICSI). DESIGN: Multicenter, single-blinded, randomized controlled trial, conducted from July 2014 to March 2017. SETTING: IVF clinics. PATIENT(S): A total of 626 women undergoing IVF treatment with or without ICSI and 222 male partners. INTERVENTIONS(S): Couples were randomly assigned to the light (control group) or regular (intervention group) Smarter Pregnancy program. Both groups filled out a baseline screening questionnaire on nutrition and lifestyle behaviors, and the intervention group received coaching tailored to inadequate behaviors during the 24-week period. MAIN OUTCOME MEASURE(S): Difference in improvement of a composite dietary and lifestyle risk score for the intake of vegetables, fruits, folic acid supplements, smoking, and alcohol use after 24 weeks of the program. RESULT(S): Compared with control subjects, women and men in the intervention group showed a significantly larger improvement of inadequate nutrition behaviors after 24 weeks of coaching. At the same time, the women also showed a significantly larger improvement of inadequate lifestyle behaviors. CONCLUSION(S): The mHealth coaching program Smarter Pregnancy is effective and improves the most important nutritional and lifestyle behaviors among couples undergoing IVF/ICSI treatment. International multicenter randomized trials are recommended to study the effect of using Smarter Pregnancy on pregnancy, live birth, and neonatal outcome. NETHERLANDS TRIAL REGISTER NUMBER: NTR4150.

Ovarian tissue cryopreservation: Low usage rates and high live-birth rate after transplantation.

INTRODUCTION: The likelihood of survival after cancer treatment among young women with cancer has increased considerably, quality of life after treatment has drawn more attention. However, in young fertile women, fertility preservation is an important issue with regard to quality of life. One of the options of fertility preservation is ovarian tissue cryopreservation. The purpose of this follow-up study is to present our clinical experiences and evaluate the long-term follow up of ovarian cryopreservation to improve future patient selection. MATERIAL AND METHODS: From July 2002 to December 2015 at the Leiden University Hospital, the Netherlands, 69 young women underwent ovarian tissue cryopreservation when they were at risk of iatrogenic premature ovarian insufficiency. Follow-up data with regard to ovarian function were obtained until October 2018, from medical records and questionnaires. RESULTS: Of the 69 women in whom ovarian tissue cryopreservation was performed, 12 died (15.9%), 57 were approached to participate, of which 6 were lost to follow up. The indications for ovarian tissue cryopreservation were malignant (81.1%) and benign (18.9%) diseases in which gonadotoxic treatment was scheduled. In total, twenty women (39.2%) are known to have premature ovarian insufficiency due to gonadotoxic treatment. Fifteen women conceived spontaneously, and delivered 25 babies. In this cohort, the usage rate of autotransplantation is 8.7% (7/69). In total, nine autotransplantations of cryopreserved ovarian tissue were performed in seven patients (of which 1 ovarian tissue cryopreservation was performed in another hospital) after which 6 babies were born to four women, giving a live-birth rate of 57%. CONCLUSIONS: Ovarian tissue cryopreservation followed by autotransplantation is an effective method to restore fertility (live-birth rate of 57%). The usage rate of 8.7% (6/69) indicates that more knowledge about the risk of premature ovarian insufficiency after gonadotoxic treatment is needed to be able to offer ovarian tissue cryopreservation more selectively.

Gonadotrophins or clomiphene citrate in couples with unexplained infertility undergoing intrauterine insemination: a cost-effectiveness analysis.

RESEARCH QUESTION: What is the cost-effectiveness of gonadotrophins compared with clomiphene citrate in couples with unexplained subfertility undergoing intrauterine insemination (IUI) with ovarian stimulation under strict cancellation criteria? DESIGN: A cost-effectiveness analysis alongside a randomized controlled trial (RCT). Between July 2013 and March 2016, 738 couples were randomized to gonadotrophins (369) or clomiphene citrate (369) in a multicentre RCT in the Netherlands. The direct medical costs of both strategies were compared. Direct medical costs included costs of medication, cycle monitoring, insemination and, if applicable, pregnancy monitoring. Non-parametric bootstrap resampling was used to investigate the effect of uncertainty in estimates. The cost-effectiveness analysis was performed according to intention-to-treat. The incremental cost-effectiveness ratio (ICER) between gonadotrophins and clomiphene citrate for ongoing pregnancy and live birth was assessed. RESULTS: The mean costs per couple were €1534 for gonadotrophins and €1067 for clomiphene citrate (mean difference of €468; 95% confidence interval [CI] €464-472). As ongoing pregnancy rates were 31% in women allocated to gonadotrophins and 26% in women allocated to clomiphene citrate (relative risk 1.16, 95% CI 0.93-1.47), the ICER was €21,804 (95% CI €11,628-31,980) per additional ongoing pregnancy with gonadotrophins and €17,044 (95% CI €8998-25,090) per additional live birth with gonadotrophins. CONCLUSIONS: Gonadotrophins are more expensive compared with clomiphene citrate in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria, without being significantly more effective.

Two live births following orthotopic ovarian tissue autotransplantation: A case report of cycle monitoring and (modified) natural-cycle IVF in one patient.

INTRODUCTION: Ovarian tissue cryopreservation (OTC) is an option to preserve fertility. This article describes the effect of cycle monitoring on the chances of pregnancy following orthotopic ovarian tissue autotransplantation. CASE PRESENTATION: A 32-year-old woman diagnosed with breast cancer underwent right-sided oophorectomy and OTC prior to chemotherapy. Three years later she was diagnosed with premature ovarian insufficiency and ovarian tissue chips were transplanted in the remaining ovary and a peritoneal window. Eight months after transplantation, activity was seen in the tissue placed in the peritoneal window. With a low natural chance of conception, modified natural-cycle (MNC) IVF was started by administration of a GnRH antagonist. Ovulation was triggered with hCG. One oocyte was retrieved by transvaginal ovum pick-up. After fertilization, a six-cell-stage embryo of good quality was transferred. This resulted in pregnancy and a healthy girl was born at 41 weeks. In the second monitored cycle after her delivery, a follicle was seen in the remaining ovary. Two weeks later a pregnancy test was positive and after an uncomplicated pregnancy a healthy boy was delivered spontaneously at 41 weeks. CONCLUSIONS: This case reports shows that MNC IVF conception after OTC is successful in patients with tissue partially placed in a peritoneal window. If the tissue placed in the peritoneal window becomes active, MNC IVF can be performed. If the tissue placed in the remaining ovary becomes active, natural conception should be pursued.

Randomized Trial of a Lifestyle Program in Obese Infertile Women.

BACKGROUND: Small lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking. METHODS: We randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization. RESULTS: We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (P<0.001). The primary outcome occurred in 27.1% of the women in the intervention group and 35.2% of those in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60 to 0.99). CONCLUSIONS: In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.).

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate - a randomised controlled trial.

BACKGROUND: Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. METHODS/DESIGN: We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). DISCUSSION: The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women. TRIAL REGISTRATION NUMBER: Netherlands Trial register NTR1449.

The LIFESTYLE study: costs and effects of a structured lifestyle program in overweight and obese subfertile women to reduce the need for fertility treatment and improve reproductive outcome. A randomised controlled trial.

BACKGROUND: In the Netherlands, 30% of subfertile women are overweight or obese, and at present there is no agreement on fertility care for them. Data from observational and small intervention studies suggest that reduction of weight will increase the chances of conception, decrease pregnancy complications and improve perinatal outcome, but this has not been confirmed in randomised controlled trials. This study will assess the cost and effects of a six-months structured lifestyle program aiming at weight reduction followed by conventional fertility care (intervention group) as compared to conventional fertility care only (control group) in overweight and obese subfertile women. We hypothesize that the intervention will decrease the need for fertility treatment, diminish overweight-related pregnancy complications, and will improve perinatal outcome. METHODS/DESIGN: Multicenter randomised controlled trial in subfertile women (age 18-39 year) with a body mass index between 29 and 40 kg/m2. Exclusion criteria are azoospermia, use of donor semen, severe endometriosis, premature ovarian failure, endocrinopathies or pre-existent hypertensive disorders.In the intervention group the aim is a weight loss of at least 5% to10% in a six-month period, to be achieved by the combination of a diet, increase of physical activity and behavioural modification. After six months, in case no conception has been achieved, these patients will start fertility treatment according to the Dutch fertility guidelines. In the control group treatment will be started according to Dutch fertility guidelines, independently of the patient's weight. OUTCOME MEASURES AND ANALYSIS: The primary outcome measure is a healthy singleton born after at least 37 weeks of gestation after vaginal delivery. Secondary outcome parameters including pregnancy outcome and complications, percentage of women needing fertility treatment, clinical and ongoing pregnancy rates, body weight, quality of life and costs.Data will be analysed according to the intention to treat principle, and cost-effectiveness analysis will be performed to compare the costs and health effects in the intervention and control group. DISCUSSION: The trial will provide evidence for costs and effects of a lifestyle intervention aiming at weight reduction in overweight and obese subfertile women and will offer guidance to clinicians for the treatment of these patients. TRIAL REGISTRATION: Dutch Trial Register NTR1530.