Abstract Obesity in women is negatively associated with reproductive outcomes such as decreased natural conception and pregnancy rate in assisted reproductive technique (ART), as well as increased risks of miscarriage and maternal and foetal complications, including risks of perinatal and neonatal death. The reproductive consequences of obesity stem from a combination of ovarian, uterine and systemic pathophysiological changes, although not all fully elucidated. These alterations contribute to reduced oocyte and embryo quality, reduced uterine receptivity and systemic inflammatory responses. Various guidelines recommend lifestyle interventions based on dietary and/or physical activity targeting at a 5 to 10% reduction in body weight as an initial step prior to fertility treatment for women with infertility and overweight or obesity. However, evidence from well powered randomised controlled trials (RCTs) assessing the effectiveness of lifestyle interventions aiming at weight loss prior to fertility treatments is scarce and not unequivocally positive with respect to reproductive outcomes. First, this presentation will focus on the effectiveness of pre-conception lifestyle intervention targeting weight loss, on reproductive outcomes documented in the latest systematic review (SR) and meta-analysis and preliminary results of an individual participant data meta-analysis (IPDMA). The latest SR in 2021 (Obesity reviews DOI: 10.1111/obr.13325) including 15 RCTs until March 2020 (N = 1852 women) suggests more weight loss in the intervention group. An increase in live birth rates (LBR) in nine RCTs (N = 1203 women) and a higher natural conception rate following lifestyle intervention compared to no intervention were reported. However, no effect of lifestyle intervention preceding ART in six RCTs (N = 1040 women). With respect to potential harm of lifestyle intervention there is no significant increased risk of early pregnancy loss. Complications during pregnancy, such as early pregnancy loss and maternal, fetal and neonatal outcomes are underreported in most included studies. The VENUS IPDMA (BMJ Open 2022;12:e065206) analyzed individual patient data of 11 RCTs of 14 eligible RCTs (N = 1903 participants; 1010 in the intervention group and 893 in the control group). Preliminary data (abstract ESHRE 2023) showed that physical activity and/or dietary interventions prior to fertility treatment resulted in more weight reduction compared to those in the control group in 11 RCTs. The intervention group, however, did not have a significantly higher rate of LBR in nine RCTs (N = 1702 participants). Compared to the control group, the intervention group had smaller waist and hip circumference, lower systolic and diastolic blood pressure, and lower triglycerides, total cholesterol, glucose, and insulin levels at the time of study follow up. Do we have a definitive answer to the question: “weight loss interventions prior to fertility treatment; does it make sense” using data of IPDMA? Shortcomings of the available evidence regarding the effectiveness and safety of dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatments will be presented. Limitations of the studies and future perspectives and challenges in this field of research will be highlighted. Finally, the question “does it make sense” is broader than the effectivity of the intervention. Do we as clinicians adopt our role as health advocates to advice and guide future parents to adopt a healthy lifestyle, with weight reduction as a result? Could this lead to a healthier lifestyle for the future of parents and children? To conclude: “does it make sense” is not an easy question to answer.

Abstract Study question Are there differences in AMH and androgens concentrations between women with PCOS who resume ovulation (RO+) and those remain anovulatory (RO-) during lifestyle intervention? Summary answer RO+ women showed significant decrease in AMH and 11β-hydroxyandrostenedione concentrations at three months, and increase in SHBG concentrations at six months compared to RO- women. What is known already Lifestyle interventions have been shown to reduce clinical and biochemical hyperandrogenism in women with PCOS. Weight loss of 5-10% may reverse anovulatory status, thereby increasing natural conception rates. However, the underlying mechanisms why some women with PCOS remain anovulatory and others resume ovulation after weight loss are unclear. Reproductive characteristics at baseline and a greater degree of change in endocrine and metabolic features with lifestyle intervention may be crucial for ovulatory response. Study design, size, duration We used data and samples originating from an RCT which examined the efficacy of a six-month lifestyle intervention prior infertility treatment compared to prompt infertility treatment on live birth rate in women with obesity. In total of 577 women with obesity were randomized between 2009 and 2012. Anovulatory women with PCOS who were allocated to the intervention arm of the original RCT (n = 97) were included in the current analysis. Participants/materials, setting, methods We defined women as ovulatory during or after intervention based on the following criteria either: (1) spontaneous pregnancy; Or (2) Treatment strategy after lifestyle intervention; expectant management; (3) or IUI treatment in natural cycles. The steroid hormones were measured using LC-MS/MS. Multilevel analysis with the adjustment of baseline measurements was used to examine differences in changes in AMH and androgens concentrations between RO + (n=34) and RO- groups (n = 61) at three and six months after intervention. Main results and the role of chance At baseline, the mean age was 27.5 ± 3.6 in RO+ group and 27.9 ± 4.1 years in RO- group (p = 0.65). The mean weight was 101.2 ± 9.5 and 105.0 ± 14.6 kg, respectively (p = 0.13). AMH concentrations showed significant differences between RO+ women and RO- women (median and IQR 4.7 [3.2; 8.3] in the RO+ group and 7.2 [5.3; 10.8] ng/mL in the RO- group, p = 0.03). Androgen concentrations did not differ between the two groups. During and after lifestyle intervention, RO+ women had significant decrease in AMH (mean difference: –1.6 ng/mL, 95%CI: –3.0 to –0.20, p = 0.03) and 11β-hydroxyandrostenedione (mean difference: –1.7 nmol/L, 95%CI: –3.1 to –0.41, p = 0.01) concentrations than RO- women at three months. SHBG concentrations were significantly increased in RO+ compared to RO- women at six months (mean difference: 11 nmol/L, 95%CI: 1.1 to 22, p = 0.03). Changes in 11-ketotestosterone (three months mean difference: –0.15 nmol/L, 95%CI: –0.49 to 0.20, p = 0.41; six months: –0.39 nmol/L, 95%CI: –1.3 to 0.57, p = 0.43) and testosterone (three months mean difference: 0.13 nmol/L, 95%CI: –0.32 to 0.57, p = 0.58; six months: –0.29 nmol/L, 95%CI: –0.81 to 0.23, p = 0.27) did not differ at three or six months between groups. Limitations, reasons for caution The indirect parameters to confirm ovulatory cycles at the end of lifestyle program and small sample size may limit the robustness of the results. Wider implications of the findings Reduction of serum AMH and androgen concentrations during lifestyle intervention is associated with recovery of ovulatory cycles. When our results are confirmed in other studies, serum AMH and androgens concentrations could be monitored during lifestyle intervention to provide individualized recommendations on resumption of ovulatory cycles in anovulatory women with PCOS. Trial registration number NTR1530

Abstract Study question Does 6 months expectant management reduces ongoing pregnancy rates compared to intrauterine insemination with ovarian stimulation (IUI-OS) in couples with unexplained subfertility? Summary answer In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of expectant management decreases ongoing pregnancy rates as compared to IUI-OS. What is known already In couples with unexplained subfertility and a poor prognosis, IUI-OS is a first line treatment. We have previously shown that in couples with unexplained subfertility and a good prognosis for natural conception (>30% in 12 months), 6 months expectant management does not reduce pregnancy changes. However, in couples with a poor prognosis for natural conception, effectiveness of IUI-OS is uncertain. Study design, size, duration We performed a non-inferiority multicentre randomised controlled trial (RCT) within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We studied couples with unexplained subfertility and a poor prognosis for natural conception. The couples were allocated in a 1:1 ratio to six months expectant management or six months IUI-OS with either clomiphene citrate or gonadotrophins. Participants/materials, setting, methods We intended to include 1091 couples. The trial was halted pre-maturely due to slow inclusion after randomisation of 178 couples. The primary outcome was ongoing pregnancy leading to a live birth with multiple pregnancy and miscarriage rate as important secondary outcomes. We calculated relative risks with 95% CI and a corresponding hazard-rate for ongoing-pregnancy-over-time based on intention-to-treat. Main results and the role of chance Between October 2016 and September 2020 92 couples were allocated to expectant management and 86 to IUI-OS. Baseline characteristics were equally distributed. Mean female age was 34 years, median duration of subfertility was 21 months. Within 6 months after randomisation, women allocated to expectant management had a lower ongoing pregnancy rate than women allocated to IUI-OS (12/92 [13.0%] vs 29/86 women [33.7%], risk ratio 0.39 (95%CI 0.21 to 0.71)). There were two ongoing twin pregnancies in the expectant management group versus none in the IUI-OS group. Of 15 clinical pregnancies in the expectant management group three miscarried (20%), of 36 clinical pregnancies in the IUI-OS group seven miscarried (19.4%) (RR 1.03 (95% CI 0.31 to 3.45)). For the outcome ongoing pregnancy, the hazard ratio for expectant management versus IUI-OS was 0.34 (95%CI 0.18 to 0.67). Limitations, reasons for caution Our trial did not reach the planned sample size and therefore the results are limited by the number of participants. As 8 women are still pregnant, in this abstract we report ongoing pregnancy rates. Live birth rates will be presented at the conference. Wider implications of the findings: In couples with unexplained subfertility and a poor prognosis for natural conception, expectant management is inferior to IUI-OS. We advise the basic work-up for subfertility to contain a prognostic assessment, and when subfertility is unexplained and natural fertility prospects are poor IUI-OS should be the preferred treatment. Trial registration number NTR5599

Abstract Study question Is health-related quality of life (HRQoL) in women with unexplained subfertility and a poor prognosis influenced by expectant management or intrauterine insemination with ovarian stimulation? Summary answer HRQoL did not differ, except for the relational domain which was lower after expectant management. Anxiety and depression disorders occurred frequently in both groups. What is known already In couples with unexplained subfertility and a poor prognosis, IUI with ovarian stimulation (IUI-OS) is a first line treatment. Not much is known about quality of live or depression and anxiety in these couples. The Fertility Quality of Life (FertiQoL) is reliable for assessment within relational and social domains, the Hospital Anxiety and Depression Scale (HADS) is a reliable tool to detect anxiety and depression disorders. Study design, size, duration We performed a multicentre RCT in couples with unexplained subfertility with a poor prognosis of conceiving naturally within one year. Women were allocated 1:1 to six months expectant management or to six months IUI-OS. HRQoL was assessed with standard self-administered psychometric measures with established reliability and validity: FertiQol and HADS. We intended to include 1091 couples but after almost 4 years, the study had to stop due to slow inclusion and therefore lack of funding. Participants/materials, setting, methods Between June 2017 and September 2020, we recruited 178 women of wich 92 were assigned expectant management and 86 IUI-OS. All women who participated and could read Dutch were eligible for the HRQoL measurements because HRQoL questionnaires in foreign languages were not yet available online. Women completed the questionnaires before randomisation, 3 and 6 months after randomisation. We used mixed model analyses to assess differences between treatment groups and the effect of time. Main results and the role of chance One hundred sixty-two women could read Dutch and were invited (162/178 (91%)). Analyzable data of the FertiQol questionnaire were available for 80% (130/162). Compared to women allocated to IUI-OS, women allocated to expectant management had a lower FertiQol score in the relational domain (mean difference –4.3 (95% CI –7.3 to –1.3) but not in the social domain (mean diff van –0.8 (95% CI –4.5 to 2.9). Data of the HADS questionnaire were available of 156 women (96% (156/162)). Both groups had comparable scores in the Anxiety (mean difference –0.20; 95% CI 0.63; –0.99 to 0.6) and Depressions score (mean difference 0.002; 95% CI –0.67 to 0.67) at all three moments. At baseline, the incidence of an anxiety disorder (definition score 8 or higher) was 19% (30/156) and increased to 30% and 29% at 3 months and 6 months respectively. The incidence of a depression disorder (definition score 8 or higher) was 5% (7/156) and increased to 16% and 18% at 3 months and 6 months respectively. The incidences of anxiety or depression disorders did not differ significantly between expectant management and IUI. Limitations, reasons for caution Our randomized controlled trial did not reach the planned sample size. The results are only applicable to women with unexplained subfertility and a poor prognosis and not to all women with unexplained subfertility. Wider implications of the findings: Although often assumed, IUI-OS does not improve HRQoL compared to expectant management in all domains. IUI might prevent loss of quality of the relationship, but the impact seems small. Future studies should look into the high incidence of anxiety and depression disorders in these women and how to support them. Trial registration number Trial register NL5455 (NTR5599)

Background In the Netherlands, couples with unexplained infertility and a good prognosis to conceive spontaneously (i.e. Hunault > 30%) are advised to perform timed intercourse for at least another 6 months. If couples fail to conceive within this period, they will usually start assisted reproductive technology (ART). However, treatment of unexplained infertility by ART is empirical and can involve significant burdens. Intentional endometrial injury, also called ‘endometrial scratching’, has been proposed to positively affect the chance of embryo implantation in patients undergoing in vitro fertilization (IVF). It might also be beneficial for couples with unexplained infertility as defective endometrial receptivity may play a role in these women. The primary aim of this study is to determine whether endometrial scratching increases live birth rates in women with unexplained infertility. Method A multicentre randomized controlled trial will be conducted in Dutch academic and non-academic hospitals starting from November 2017. A total of 792 women with unexplained infertility and a good prognosis for spontaneous conception < 12 months (Hunault > 30%) will be included, of whom half will undergo endometrial scratching in the luteal phase of the natural cycle. The women in the control group will not undergo endometrial scratching. According to Dutch guidelines, both groups will subsequently perform timed intercourse for at least 6 months. The primary endpoint is cumulative live birth rate. Secondary endpoints are clinical and ongoing pregnancy rate; miscarriage rate; biochemical pregnancy loss; multiple pregnancy rate; time to pregnancy; progression to intrauterine insemination (IUI) or IVF; pregnancy complications; complications of endometrial scratching; costs and endometrial tissue parameters associated with reproductive success or failure. The follow-up duration is 12 months. Discussion Several small studies show a possible beneficial effect of endometrial scratching in women with unexplained infertility trying to conceive naturally or through IUI. However, the quality of this evidence is very low, making it unclear whether these women will truly benefit from this procedure. The SCRaTCH-OFO trial aims to investigate the effect of endometrial scratching on live birth rate in women with unexplained infertility and a good prognosis for spontaneous conception < 12 months. Trial registration NTR6687 , registered August 31st, 2017. Protocol version Version 2.6, November 14th, 2018.

Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called ‘scratching’, has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle.

Journal de Gynecologie Obstetrique et Biologie de la Reproduction - Vol. 34 - N° SUP7 - p. 5-6