High Sperm DNA Fragmentation Index is associated with an increased risk of preeclampsia following assisted reproduction treatment.

OBJECTIVE: To study the association between sperm DNA fragmentation index (DFI) and the odds of preeclampsia and other adverse perinatal outcomes after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. DESIGN: A prospective cohort study including infertile couples undergoing conventional IVF or ICSI treatment and their children. Data regarding preeclampsia and perinatal outcomes were derived from the Swedish National Birth Register. SUBJECTS: 1594 infertile couples undergoing IVF or ICSI treatment and their 1660 children conceived by assisted reproduction. EXPOSURE: Sperm DNA fragmentation index measured by Sperm Chromatin Structure Assay. MAIN OUTCOME MEASURES: The primary outcome was preeclampsia. Secondary outcomes were preterm birth, low birth weight, low Apgar score, and small for gestational age. RESULTS: With DFI < 20% as a reference, the OR for preeclampsia was statistically significantly increased in the group with DFI ≥ 20% when IVF was used as fertilization method (OR 2.2; 95% CI 1.1 to 4.4; p = 0.02). Already at DFI levels ≥ 10%, in IVF pregnancies, preeclampsia odds were increased in a dose-response manner, from a prevalence of 3.1% in the reference group to more than 10% among those with DFI of 30% or higher. The DFI was not associated with preeclampsia odds in the ICSI group. In the entire cohort, DFI ≥ 20% was associated with an increased OR of preterm birth (OR 1.4; 95% CI 1.0 to 2.0; p = 0.03). CONCLUSION: High DNA fragmentation index was associated with increased odds of preterm birth and, in IVF pregnancies, also increased odds of preeclampsia.

Progesterone concentrations on blastocyst transfer day in modified natural cycle frozen embryo transfer cycles.

RESEARCH QUESTION: Are serum progesterone concentrations on the day of modified natural cycle (mNC) frozen blastocyst transfer (FET) without luteal phase support (LPS) associated with clinical pregnancy rate (CPR)? DESIGN: Data were collected between January 2019 and October 2022 as a sub-study of an ongoing randomized controlled trial assessing pregnancy outcomes in mNC-FET. The sub-study included all women (n = 209) randomized to mNC-FET without LPS at the time of data extraction. Participants were aged 18-41 years, had regular menstrual cycles and underwent mNC-FET treatment with single-blastocyst transfer. Associations between the serum progesterone concentration on the day of blastocyst transfer and CPR, pregnancy rate and pregnancy loss rate (PLR) were examined between groups with low and higher progesterone concentrations using the 25th and 10th percentiles as cut-offs. Multivariate logistic regression analyses were performed to adjust for potential confounding factors. RESULTS: Progesterone concentrations on the day of blastocyst transfer in mNC-FET without LPS ranged from 4.9 to 91.8 nmol/l, with the 25th and 10th percentiles at 29.0 nmol/l and 22.5 nmol/l, respectively. Serum progesterone concentrations did not differ between women with or without a clinical pregnancy (mean [SD] 38.5 [14.0] versus 36.8 [12.4] nmol/l; P = 0.350). Furthermore, the CPR, pregancy rate and PLR were similar in women with low or high progesterone concentrations when using the 25th or the 10th progesterone percentile as cut-off. Multivariate regression analyses showed no association between progesterone concentrations and CPR. CONCLUSIONS: No association was found between progesterone concentration on the day of blastocyst transfer and pregnancy outcome in women undergoing mNC-FET without progesterone LPS.

Single mothers by choice - experiences of single women seeking treatment at a public fertility clinic in Denmark: A pilot study.

PROBLEM: There has been an increase in the number of single women deciding to have children through the use of medically assisted reproduction (MAR). These women are referred to as 'single mothers by choice' (SMC). BACKGROUND: Previous studies have shown how SMC can feel stigmatised. AIM: Explore if single women seeking fertility treatment in Denmark feel stigmatised. METHODS: Six single women undergoing MAR at a public fertility clinic in Denmark were interviewed. The interviews were audiotaped, anonymised, and transcribed in full, after provided written consent by the participants to take part in the study. Data were analysed using qualitative content analysis. FINDINGS: The women would have preferred to have a child in a relationship with a partner. Despite their dream of the nuclear family meaning a family group consisting of two parents and their children (one or more), the women choose to become SMC because motherhood was of such importance, and they feared they would otherwise become too old to have children. The participants did not experience stigma or negative responses to their decision, but they all had an awareness of the prejudices other people might have towards SMC. CONCLUSION: This study contributes to the understanding of the experiences of single women seeking fertility treatment in a welfare state where there are no differences in the possibilities for different social classes to seek MAR.

The prevalence of late-follicular phase progesterone elevation and impact on the ongoing pregnancy rate after fresh and frozen blastocyst transfer. Sub-study of an RCT.

The effect of late-follicular phase progesterone elevation (LFPE) during ovarian stimulation on reproductive outcomes in ART treatment remains controversial, but recent studies indicate lower pregnancy rates with rising progesterone levels. This study aims to investigate the prevalence of late-follicular phase progesterone elevation (LFPE) and possible impact on ongoing pregnancy rate after fresh or frozen blastocyst transfer in a sub-study setting of a randomised controlled trial. A total of 288 women were included (n=137 and n=151 in the fresh transfer and freeze-all group, respectively). Among these 11(3.8%) had a progesterone level ≥1.5 ng/ml, and 20(6.9%) had a progesterone level ≥1.2 ng/ml on trigger day. Spline regression analysis showed no significant effect of late follicular phase progesterone levels on ongoing pregnancy. In the multivariate regression analysis (n = 312) only age, but not progesterone level on trigger day was significantly associated with ongoing pregnancy. In conclusion, in a clinical setting with moderate gonadotrophin stimulation and well-defined trigger and fresh transfer cancellation criteria, the prevalence of women with LFPE ≥1.5 ng/ml was low and did not indicate the clinical value of routine measurement of progesterone in the late follicular phase.

Psychosocial wellbeing shortly after allocation to a freeze-all strategy compared with a fresh transfer strategy in women and men: a sub-study of a randomized controlled trial.

STUDY QUESTION: Is the psychosocial wellbeing affected in women and men shortly after allocation to a freeze-all strategy with postponement of embryo transfer compared to a fresh transfer strategy? SUMMARY ANSWER: In general, psychosocial wellbeing (i.e. emotional reactions to the treatment, quality-of-life, infertility-related stress, and marital benefit) was similar in women and men allocated to a freeze-all versus those allocated to a fresh-transfer strategy 6 days after disclosure of treatment strategy (i.e. 4 days after oocyte retrieval), although women in the freeze-all group reported a slightly higher degree of depressive symptoms and mood swings compared to women in the fresh transfer group. WHAT IS KNOWN ALREADY: The use of a freeze-all strategy, i.e. freezing of the entire embryo cohort followed by elective frozen embryo transfer in subsequent cycles has increased steadily over the past decade in assisted reproductive technology (ART). This strategy essentially eliminates the risk of ovarian hyperstimulation syndrome and has proven beneficial regarding some reproductive outcomes in subgroups of women. However, patients experience a longer time interval between oocyte retrieval and embryo transfer, hence a longer time to pregnancy, possibly adding additional stress to the ART treatment. So far, little focus has been on the possible psychosocial strains caused by postponement of embryo transfer. STUDY DESIGN, SIZE, DURATION: This is a self-reported questionnaire based sub-study of a multicentre randomized controlled trial (RCT) including 460 women and 396 male partners initiating their first, second, or third treatment cycle of invitro fertilisation or intracytoplasmic sperm injection (ICSI) from May 2016 to September 2018. This sub-study was included in the primary project protocol and project plan for the RCT, as psychosocial wellbeing was considered a secondary outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women from eight public fertility clinics in Denmark and Sweden and one private clinic in Spain were randomized in a 1:1 ratio on the day of inclusion (menstrual cycle day 2 or 3) to either a freeze-all strategy with postponement of embryo transfer to a subsequent modified natural menstrual cycle or a fresh transfer strategy with embryo transfer in the hormone stimulated cycle. Treatment allocation was blinded until the day of the ovulation trigger. Women and their male partners were asked to complete a validated self-reported questionnaire 6 days after unblinding of treatment group allocation, corresponding to 4 days after oocyte retrieval, investigating their psychosocial wellbeing related to the treatment defined as emotional reactions to the treatment, quality-of-life, infertility-related stress, and marital benefit. The questionnaire included items from the Copenhagen Multi-Centre Psychosocial Infertility (COMPI) Fertility Problem Stress Scales and the COMPI Marital Benefit Measure. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were comparable between the two groups for both women and men. In total, response rates were 90.7% for women and 90.2% for men. In the freeze-all group, 207 women and 179 men completed the questionnaire compared with 204 women and 178 men in the fresh transfer group. Men in the two treatment groups did not differ in any of the explored aspects of psychosocial wellbeing (i.e. emotional reactions to the treatment, quality-of-life, infertility-related stress, and marital benefit) 6 days after disclosure of treatment strategy. Women in the freeze-all group reported a slightly higher degree of depressive symptoms (P = 0.045) and mood swings (P = 0.001) (i.e. variables included in 'emotional reactions to treatment') compared to women in the fresh transfer group. When adjusted for multiple testing, depressive symptoms were no longer significantly different between the two groups. No additional differences in psychosocial wellbeing were found. Self-reported quality-of-life during treatment was also rated as similar between the two groups in both women and men, but was slightly lower than they would rate their quality-of-life when not in fertility treatment. LIMITATIONS, REASONS FOR CAUTION: Although response rates were high, selection bias cannot be excluded. As this study was an RCT, we assume that psychosocial characteristics of the participants were equally distributed in the two groups, thus it is unlikely that the identified psychosocial differences between the freeze-all and fresh transfer group were present already at baseline. Furthermore, the questionnaire was completed as a one-time assessment 4 days after oocyte retrieval, thus not reflecting the whole treatment process, whereas an assessment after the full completed treatment cycle is needed to draw firm conclusions about the psychosocial consequences of the whole waiting period. However, a question posted that late would be highly biased on whether or not a pregnancy had been achieved. WIDER IMPLICATIONS OF THE FINDINGS: The results indicate that individuals in the freeze-all group exhibited slightly higher levels of depressive symptoms and mood swings compared to those in the fresh transfer group. Nevertheless, it is important to note that any worries related to potential emotional strains stemming from delaying embryo transfer should not overshadow the adoption of a freeze-all approach in cases where it is clinically recommended. As long as patients are provided with comprehensive information about the treatment strategy before initiating the process, it is worth emphasising that other aspects of psychosocial wellbeing were comparable between the two groups. STUDY FUNDING/COMPETING INTEREST(S): The study is part of the Reprounion collaborative study, co-financed by the European Union, Interreg V Öresund-Kattegat-Skagerrak. L.P. reports financial support from Merck A/S. H.S.N. reports grants from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, Ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond and Independent Research Fund Denmark and personal fees from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, Cook Medical, IBSA Nordic and Gedeon Richter. H.S.N is founder and chairman of the Maternity Foundation and co-developed the Safe Delivery App (non-profit). N.C.F. reports grants from Gedeon Richter, Merck A/S, Cryos International and financial support from Ferring Pharmaceuticals, Merck A/S and Gedeon Richter. N.C.F. is chairman in the steering committee for the guideline groups for The Danish Fertility Society (non-profit). P.H. reports honoraria from Merch A/S, IBSA Nordic and Gedeon Richter. A.L.M.E. reports grants and financial support from Merck A/S and Gedeon Richter. A.P. reports grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and personal fees from Preglem S.A., Novo Nordic Foundation, Ferring Pharmaceuticals, Gedeon Richter, Cryos International, Merch A/S, Theramex and Organon and the lend of embryoscope to the institution from Gedeon Richter. All other authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02746562.

Low-grade inflammation is negatively associated with live birth in women undergoing IVF.

RESEARCH QUESTION: Is low-grade inflammation, detected by C-reactive protein (CRP), a marker of IVF outcome addressing both blastocyst quality and pregnancy outcome? DESIGN: This sub-study of a multicentre randomized controlled trial included 440 women undergoing IVF treatment with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Serum CRP was measured on cycle day 2-3 (baseline) and on the day of ovulation triggering. The association between CRP concentrations and reproductive outcomes (number of retrieved oocytes, number of good-quality blastocysts, pregnancy, pregnancy loss and live birth), were analysed, adjusting for relevant confounders. RESULTS: A negative association was found between higher baseline CRP concentrations and live birth rate (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62-0.96, P = 0.02) and higher CRP concentrations at baseline were associated with pregnancy loss among women who conceived (OR 1.37, 95% CI 1.07-1.76, P = 0.01). When testing for a specific cut-off, CRP concentrations above 2.34 (the highest quartile) were more likely to be associated with pregnancy loss (P = 0.02) and a lower chance of live birth (P = 0.04) compared with the lowest quartile. No associations were found between CRP concentrations and pregnancy outcomes on the day of ovulation triggering, and there were no associations between CRP concentrations and the number of good-quality blastocysts. CONCLUSIONS: Higher CRP concentrations at cycle day 2-3, before starting ovarian stimulation, are negatively associated with chance of live birth, possibly because of an increased risk of pregnancy loss. No association was found between the number of good-quality blastocysts and CRP concentration. More studies are needed to investigate the impact of low-grade inflammation.

Immediate versus postponed single blastocyst transfer in modified natural cycle frozen embryo transfer (mNC-FET): a study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Today, it is widespread practice to postpone frozen embryo transfer (FET) in a modified natural cycle (mNC) for at least one menstrual cycle after oocyte retrieval and failed fresh embryo transfer or freeze-all. The rationale behind this practice is the concern that suboptimal ovarian, endometrial or endocrinological conditions following ovarian stimulation may have a negative impact on endometrial receptivity and implantation. However, two recent systematic reviews and meta-analyses based on retrospective data did not support this practice. As unnecessary delay in time to transfer and pregnancy should be avoided, the aim of this study is to investigate if immediate single blastocyst transfer in mNC-FET is non-inferior to standard postponed single blastocyst transfer in mNC-FET in terms of live birth rate. METHODS AND ANALYSIS: Multicentre randomised controlled non-blinded trial including 464 normo-ovulatory women aged 18-40 years undergoing single blastocyst mNC-FET after a failed fresh or freeze-all cycle. Participants are randomised 1:1 to either FET in the first menstrual cycle following the stimulated cycle (immediate FET) or FET in the second or subsequent cycle following the stimulated cycle (postponed FET). The study is designed as a non-inferiority trial and primary analyses will be performed as intention to treat and per protocol. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Scientific Ethical Committee of the Capital Region of Denmark (J-nr.: H-19086300). Data will be handled according to Danish law on personal data protection in accordance with the general data protection regulation. Participants will complete written consent forms regarding participation in the study and storage of blood samples in a biobank for future research. The study will be monitored by a Good Clinical Practice (GCP)-trained study nurse not otherwise involved in the study. The results of this study will be disseminated by publication in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04748874; Pre-results.

Embryo Morphokinetics and Blastocyst Development After GnRH Agonist versus hCG Triggering in Normo-ovulatory Women: a Secondary Analysis of a Multicenter Randomized Controlled Trial.

Gonadotropin-releasing hormone agonist (GnRHa) for final oocyte maturation, along with vitrification of all usable embryos followed by transfer in a subsequent frozen-thawed cycle, is the most effective strategy to avoid ovarian hyperstimulation syndrome (OHSS). However, less is known about the ovulation induction triggers effect on early embryo development and blastocyst formation. This study is a secondary analysis of a multicenter, randomized controlled trial, with the aim to compare embryo development in normo-ovulatory women, randomized to GnRHa or human chorionic gonadotropin (hCG) trigger. In all, 4056 retrieved oocytes were observed, 1998 from the GnRHa group (216 women) and 2058 from the hCG group (218 women). A number of retrieved oocytes, mature and fertilized oocytes, and high-quality embryos and blastocysts were similar between the groups. A sub-analysis in 250 women enrolled at the main trial site including 2073 oocytes was conducted to compare embryo morphokinetics and cleavage patterns with EmbryoScope time-lapse system. In total, 1013 oocytes were retrieved from the GnRHa group (124 women) and 1060 oocytes were retrieved from the hCG group (126 women). Morphokinetic parameters and cleavage patterns were comparable between the groups. However, embryos derived from the GnRHa group were less likely to perform rolling during their development than the embryos from the hCG trigger group (OR = 0.41 (95%CI 0.25; 0.67), p-value 0.0003). The comparable results on embryo development and utilization rates between the GnRHa and hCG triggers is of clinical relevance to professionals and infertile patients, when GnRHa trigger and freeze-all is performed to avoid OHSS development. ClinicalTrials.gov Identifier: NCT02746562.

HCG Trigger After Failed GnRH Agonist Trigger Resulted in Two Consecutive Live Births: A Case Report.

Background: Failed gonadotropin-releasing hormone (GnRH) agonist trigger with no oocyte retrieved during aspiration of several follicles is a rare but recurrent situation that can be rescued by the termination of the aspiration procedure, retriggering by human chorion gonadotropin (hCG), and repeated oocyte pickup 36 h later. Failed GnRH agonist trigger is frustrating and unsatisfactory, and fertility doctors must be aware of possible hCG retriggering and retained opportunity for successful cycle outcome. Objective: In this case report, we present a woman who experienced failed GnRH agonist trigger and rescue hCG retrigger followed by two consecutive live births after frozen-thawed single blastocyst transfers. Methods: A case report. Results: Two healthy children were born in 2018 and 2020, respectively as a result of controlled ovarian stimulation for IVF, failed GnRH agonist trigger followed by hCG re-trigger, and successful retrieval of 25 oocytes. Conclusion: Retriggering with hCG after failed GnRH agonist trigger can result in consecutive live births, and such knowledge can prevent cycle cancellation and patient discouragement. Knowledge on retriggering with hCG and consecutive live births after failed GnRH agonist trigger can prevent cycle cancellation and patient discouragement.

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

OBJECTIVE: To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment. DESIGN: Multicentre, randomised controlled superiority trial. SETTING: Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain. PARTICIPANTS: 460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection. INTERVENTIONS: Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure. MAIN OUTCOME MEASURES: The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle. RESULTS: Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) v 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group. CONCLUSIONS: In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present. TRIAL REGISTRATION: Clinicaltrials.gov NCT02746562.

Endometrial scratch injury with office hysteroscopy before IVF/ICSI: A randomised controlled trial.

OBJECTIVE: Endometrial scratch injury (ESI) has been proposed to improve endometrial receptivity and thereby increase implantation rates in assisted reproductive technology (ART) treatment. ESI has been widely incorporated into clinical practice despite inconclusive evidence of its effect on reproductive outcomes. We aimed to assess pregnancy and live birth rates in subfertile women receiving ESI before IVF treatment in comparison to controls. STUDY DESIGN: This was a randomised controlled trial (RCT) with no blinding of participants, investigators or health care personnel. Women in ART treatment were allocated to either office hysteroscopy with ESI (ESI group) or no intervention (control group). In total 184 women in IVF/ICSI treatment with minimum one previous failed IVF/ICSI cycle, were included in the final analysis. The primary outcome was positive serum hCG (s-hCG). Secondary outcomes were ongoing pregnancy and live birth rate. Only per-protocol analyses were performed as all patients included at one centre had to be excluded. The trial is registered at ClinicalTrials.gov, NCT01743391. RESULTS: Our results showed a non-significant increase in positive s-hCG (OR 1.23, 95 % CI (0.65-2.33)), ongoing pregnancy (OR 1.52, 95 % CI (0.73-3.17)), and live birth rates (OR 1.69, 95 % CI (0.78-3.64)) per randomised woman between the ESI and the control group. CONCLUSION: We observed no significant differences in positive s-hCG or other reproductive outcomes in the ESI vs. the control group. While the crude estimates of positive reproductive outcomes were higher in the ESI group, statistical significance was not reached, and the study was not powered to show smaller differences. However, data from this study will be re-evaluated in the context of an individual participant data meta-analysis (IPD-MA) of RCTs on ESI.

Contribution of recruitable follicles to circulating anti-Müllerian hormone levels following maximal gonadotrophin stimulation in patients with limited ovarian reserve.

In women, the majority of anti-Müllerian hormone (AMH) measured in serum originate from small antral follicles measuring 2-10 mm. In gonadotrophin-stimulated cycles prior to assisted reproductive technology (ART), most of the recruitable follicles develop beyond 10 mm in size and thus lose their AMH secretion capacity causing declining serum AMH levels. The aim of this study was to define the residual serum AMH level after elimination of the AMH producing recruitable follicles following maximal gonadotrophin stimulation. We measured serum AMH and number of follicles according to size at several time points during a cycle of maximal gonadotrophin stimulation (fixed dose of 300 IE HP-hMG) in 107 women with low AMH (median AMH 5 pmol/L, interquartile range (IQR) 3.3-8.3). We found that AMH decreased gradually and reached a minimum level of -55.4% (95% CI -59.6; -50.7) of the baseline value four days after ovulation trigger. Our findings suggest that the residual AMH production origins from pre-antral and small antral follicles not visible by sonography and that they account for up to 40% of the circulating AMH.

Perinatal outcomes in 521 gestations after fresh and frozen cycles: a secondary outcome of a randomized controlled trial comparing GnRH antagonist versus GnRH agonist protocols.

RESEARCH QUESTION: Are perinatal outcomes different after treatment with the gonadotrophin-releasing hormone (GnRH) antagonist versus the long GnRH agonist protocol for IVF? DESIGN: Perinatal outcomes were secondary outcomes in a large Phase IV, dual-centre, open-label, randomized controlled trial to compare GnRH antagonist and long GnRH agonist protocols in women <40 years undergoing their first assisted reproductive technology treatment. Women (n = 1050) were randomized in a ratio 1:1 from January 2009 to December 2013 and followed until December 2016. All fresh and frozen embryo transfer (FET) cycles from a single oocyte aspiration, resulting in a gestation (human chorionic gonadotrophin >10 IU/l) were included (n = 521). Data were analysed to compare preterm birth [PTB] (<37 weeks), very PTB (<32 weeks), low birthweight [LBW] (<2500 g) and very LBW (<1500 g) rates among singleton live births in GnRH antagonist versus agonist protocol. RESULTS: Similar perinatal outcomes were found after both protocols. In singletons after fresh embryo transfer, mean gestational age at delivery was 39.1 ± 2.49 versus 39.3 ± 1.90 (P = 0.67) and very PTB rates 1.9% versus 0% (P = 0.17). Mean birthweight was 3264 ± 662 g in the antagonist and 3341 ± 562 g in the agonist group (P = 0.37). LBW was found in 12.4% versus 7% (P = 0.19) and very LBW in 2.9% versus 1% (P = 0.34). In FET cycles, the perinatal outcomes were similar. Small for gestational age and large for gestational age rates were similar in both protocols for singleton live births after fresh and FET. CONCLUSIONS: Perinatal outcomes are similar after the GnRH antagonist versus GnRH agonist protocols for IVF. The choice of the GnRH analogue in ovarian stimulation should be based solely on optimizing the chance of pregnancy and not on risks in perinatal outcomes.

Low semen quality and experiences of masculinity and family building.

INTRODUCTION: Infertility is a concern for men and women. There is limited knowledge on how male factor infertility affects the couple in fertility treatment. The aim of this study was to explore how severe male factor infertility affects men's sense of masculinity, the couple's relationship and intentions about family formation. MATERIAL AND METHODS: Semi-structured qualitative interview study at the Fertility Clinic at Copenhagen University Hospital, Hvidovre, Denmark. Ten men with very poor semen quality initiating fertility treatment were interviewed between November 2014 and May 2015. Data were analyzed using qualitative content analysis. RESULTS: Three themes were identified: "Threatened masculinity", "Being the strong one: impact on the couple" and "Consideration of family building options: a chapter not willing to start". The men felt that they could not fulfill their role as a man. Some couples had conflicts and discussions because the women in general wanted to talk more about infertility than the men. The men focused on having a biological child. They wanted to focus on achieving biological parenthood and postpone consideration of other family building options such as adoption or the use of semen donation in order to become a parent. CONCLUSIONS: The consequence of severe male factor infertility was a threatened sense of masculinity. Fertility specialists and nurses should recognize the impact of male infertility and create space to give their patients an opportunity to verbalize their concerns and questions related to male factor infertility and the different challenges that the couple faces during the fertility treatment.

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.

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. 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.

Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial.

INTRODUCTION: Pregnancy rates after frozen embryo transfer (FET) have improved in recent years and are now approaching or even exceeding those obtained after fresh embryo transfer. This is partly due to improved laboratory techniques, but may also be caused by a more physiological hormonal and endometrial environment in FET cycles. Furthermore, the risk of ovarian hyperstimulation syndrome is practically eliminated in segmentation cycles followed by FET and the use of natural cycles in FETs may be beneficial for the postimplantational conditions of fetal development. However, a freeze-all strategy is not yet implemented as standard care due to limitations of large randomised trials showing a benefit of such a strategy. Thus, there is a need to test the concept against standard care in a randomised controlled design. This study aims to compare ongoing pregnancy and live birth rates between a freeze-all strategy with gonadotropin-releasing hormone (GnRH) agonist triggering versus human chorionic gonadotropin (hCG) trigger and fresh embryo transfer in a multicentre randomised controlled trial. METHODS AND ANALYSIS: Multicentre randomised, controlled, double-blinded trial of women undergoing assisted reproductive technology treatment including 424 normo-ovulatory women aged 18-39 years from Denmark and Sweden. Participants will be randomised (1:1) to either (1) GnRH agonist trigger and single vitrified-warmed blastocyst transfer in a subsequent hCG triggered natural menstrual cycle or (2) hCG trigger and single blastocyst transfer in the fresh (stimulated) cycle. The primary endpoint is to compare ongoing pregnancy rates per randomised patient in the two treatment groups after the first single blastocyst transfer. ETHICS AND DISSEMINATION: The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committees in Denmark and Sweden. The results of the study will be publically disseminated. TRIAL REGISTRATION NUMBER: NCT02746562; Pre-results.

A randomized controlled trial comparing the efficacy and safety of two HMG preparations gaining their LH bioactivity from different HCG sources.

In this prospective, controlled, randomized, multicentre, non-inferiority study, efficacy and safety of two HMG preparations (Menopur®- Ferring and Meriofert®- IBSA Institut Biochimique SA) for ovarian stimulation were compared (270 women undergoing IVF aged between 18 and 39 years; BMI 30 kg/m2 or less; less than three prior completed assisted reproduction technique cycles). A standard long down-regulation with gonadotrophin-releasing hormone agonist protocol, with HCG triggering was used; primary end-point was total number of oocytes retrieved; attention was paid toovarian hyperstimulation syndrome (OHSS). No statistically significant differences between the treatment groups were reported for most of the clinically significant end-points, including embryo quality, fertilization rate, implantation rate, ongoing pregnancy rate and live birth rate. Total number of oocytes retrieved was higher in the new HMG group compared with the reference (11.6 ± 6.6 and 9.7 ± 5.9, respectively, with a 95% CI of the difference equal +0.43 to +3.43). Increased number of oocytes was obtained through a shorter stimulation, but HMG units per oocyte retrieved were equivalent. The safety profile of the products for frequency of ovarian hyperstimulation syndrome was the same. This study showed that the new HMG preparation is a viable alternative for conducting ovarian stimulation in IVF cycles.

Predictive value of plasma human chorionic gonadotropin measured 14 days after Day-2 single embryo transfer.

INTRODUCTION: Prediction of pregnancy outcome after in vitro fertilization is important for patients and clinicians. Early plasma human chorionic gonadotropin (p-hCG) levels are the best known predictor of pregnancy outcome, but no studies have been restricted to single embryo transfer (SET) of Day-2 embryos. The aim of the present study was to investigate the predictive value of p-hCG measured exactly 14 days after the most commonly used Day-2 SET on pregnancy, delivery, and perinatal outcome. MATERIAL AND METHODS: A retrospective analysis of prospectively collected data on 466 women who had p-hCG measured exactly 14 days after Day-2 SET during a randomized trial including 1050 unselected women (aged 18-40 years) undergoing their first in vitro fertilization/ intracytoplasmic sperm injection treatment. RESULTS: The p-hCG predicted clinical pregnancy [area under the curve (AUC) 0.953; 95% CI 0.915-0.992] significantly better than ongoing pregnancy (AUC 0.803, 95% CI 0.717-0.890) and delivery (AUC 0.772, 95% CI 0.691-0.854). Women with p-hCG levels in the lowest quartile had significantly lower clinical pregnancy, ongoing pregnancy, and delivery rates (p < 0.001), whereas the pregnancy outcome and post-clinical pregnancy loss remained similar throughout the three highest p-hCG quartiles. The p-hCG level was related to neither birthweight nor gestational age at delivery. CONCLUSIONS: Clinical pregnancy is significantly better predicted by p-hCG compared with ongoing pregnancy and delivery. Clinical pregnancy rates, ongoing pregnancy rates, and delivery rates remained similar throughout the three highest p-hCG quartiles with no trend towards "the higher the better".

Effect of women's age on embryo morphology, cleavage rate and competence-A multicenter cohort study.

This multicenter cohort study on embryo assessment and outcome data from 11,744 IVF/ICSI cycles with 104,830 oocytes and 42,074 embryos, presents the effect of women's age on oocyte, zygote, embryo morphology and cleavage parameters, as well as cycle outcome measures corrected for confounding factors as center, partner's age and referral diagnosis. Cycle outcome data confirmed the well-known effect of women's age. Oocyte nuclear maturation and proportion of 2 pro-nuclear (2PN) zygotes were not affected by age, while a significant increase in 3PN zygotes was observed in both IVF and ICSI (p<0.0001) with increasing age. Maternal age had no effect on cleavage parameters or on the morphology of the embryo day 2 post insemination. Interestingly, initial hCG value after single embryo transfer followed by ongoing pregnancy was increased with age in both IVF (p = 0.007) and ICSI (p = 0.001) cycles. For the first time, we show that a woman's age does impose a significant footprint on early embryo morphological development (3PN). In addition, the developmentally competent embryos were associated with increased initial hCG values as the age of the women increased. Further studies are needed to elucidate, if this increase in initial hCG value with advancing maternal age is connected to the embryo or the uterus.

Vaginal pressure during daily activities before and after vaginal repair.

The objective of the study was to measure vaginal pressure during various daily activities in patients before and after vaginal surgery for pelvic organ prolapse, searching data for evidence-based activity guidelines. Vaginal pressure (VP) was studied in 23 patients during activities such as rest, pelvic floor contraction (PFC), coughing, Valsalva, rising from sitting to standing and lifting 2 and 5 kg with four different lifting techniques. VP was measured before, 1-5 days and 4-6 weeks after vaginal repair. Mean VP was four to five times higher during coughing and Valsalva compared to PFC and lifting 2 and 5 kg. Lifting in the walking position created a slightly higher VP compared to other lifting techniques, which did not differ. The VP did not increase when lifting 5 kg compared to 2 kg. Mean VP during coughing and Valsalva were significantly lower 1-5 days after the operation. VP was not related to the type of vaginal repair. The results imply that post-operative counselling should concentrate more on treating chronic cough and constipation than restrictions of moderate physical activities.