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.

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.

Letrozole in fertility treatment.

This review describes the current evidence regarding the putative indications of letrozole (LTZ) in fertility treatment. Prior to intrauterine insemination, LTZ is recommended in women with normogonadotrophic oligo-anovulation. In ovulatory women, LTZ is equal to clomiphene and may be used instead of exogenous gonadotrophin. LTZ may be used as co-treatment in poor responders prior to in vitro fertilization/intracytoplasmic sperm injection. In addition, LTZ prior to frozen-thawed embryo transfer is increasingly used in women with normogonadotrophic oligo-anovulation.

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.

Does luteal phase progesterone supplementation affect physical and psychosocial well-being among women undergoing modified natural cycle-FET? A sub-study of a randomized controlled trial.

STUDY QUESTION: Are there any differences in physical and psychosocial well-being among women undergoing modified natural cycle frozen embryo transfer (mNC-FET) with or without vaginal progesterone as luteal phase support (LPS)? SUMMARY ANSWER: Women undergoing mNC-FET with vaginal progesterone supplementation were more likely to experience physical discomfort but there was no difference in psychosocial well-being between the two groups. WHAT IS KNOWN ALREADY: mNC-FET can be carried out with or without vaginal progesterone as LPS, which has several side-effects. It is commonly known that fertility treatment can cause stress and psychosocial strain, however, most studies on this subject are conducted in fresh cycle regimes, which differ from NC-FET and results may not be comparable. STUDY DESIGN, SIZE, DURATION: This is a sub-study of an ongoing RCT investigating whether progesterone supplementation has a positive effect on live birth rate in mNC-FET. The RCT is conducted at eight fertility clinics in Denmark from 2019 and is planned to end primo 2024. The sub-study is based on two questionnaires on physical and psychosocial well-being added to the RCT in August 2019. On the time of data extraction 286 women had answered both questionnaires. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had answered both questionnaires were included in the sub-study. Participants were equally distributed, with 143 in each of the two groups. Participants in both groups received the same questionnaires at two time-points: on cycle day 2-5 (baseline) and after blastocyst transfer. Participants in the progesterone group had administered progesterone for 7 days upon answering the second questionnaire. All items in the questionnaires were validated. Items on psychosocial well-being originate from the Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scale (COMPI-FPSS) and from the Mental Health Inventory-5. MAIN RESULTS AND THE ROLE OF CHANCE: Women receiving progesterone experienced more vaginal itching and/or burning than women in the non-progesterone group (P < 0.001). Women in the progesterone group also experienced more self-reported vaginal yeast infection, this was, however, not significant after adjustment for multiple testing (P/adjusted P = 0.049/0.881). No differences regarding psychosocial well-being were found between the two groups. Within the progesterone group, a shift toward feeling less 'downhearted and blue' was found when comparing response distribution at baseline and after blastocyst transfer (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: All items on physical symptoms were self-reported. The item on vaginal yeast infection was therefore not diagnosed by a doctor. Inclusion in the study required a few extra visits to the clinic, participants who felt more burdened by fertility treatment might have been more likely to decline participation. Women who experienced a lot of side-effects to progesterone prior to this FET cycle, might be less likely to participate. WIDER IMPLICATIONS OF THE FINDINGS: Our results are in line with previous known side-effects to progesterone. Physical side-effects of progesterone should be considered before administration. STUDY FUNDING/COMPETING INTEREST(S): The RCT is fully supported by Rigshospitalet's Research Foundation and a grant from Gedeon Richter. Gedeon Richter were not involved in the design of protocol nor in the conduction of the study or analysis of results. A.P., L.P., and N.I.-C.F. report grants from Gedeon Richter, Ferring and Merck with no relations to this study. N.I.-C.F. has received travel support from Ferring, Merck A/S, & Gideon Richter, and is the head of the steering committee for the Danish Fertility Guidelines made by the members of from the Danish Fertility Society. A.P. reports consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, honoraria from Gedeon Richter, Ferring, Merck A/S, Theramex, and Organon, has received travel support from Gedeon Richter (payment to institution), participated on an advisory board for Preglem and was loaned an embryoscope from Gedeon Richter to their institution. A.L.S. has stock options for Novo Nordisk B A/S. B.A. have received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. TRIAL REGISTRATION NUMBER: The RCT is registered on ClinicalTrials. gov (NCT03795220) and in EudraCT (2018-002207-34).

The future of frozen-thawed embryo transfer in hormone replacement therapy cycles.

PURPOSE OF REVIEW: This review focuses on the efficacy of letrozole stimulated frozen-thawed embryo transfer (FET) compared to hormone replacement therapy (HRT) FET in women with polycystic ovarian syndrome (PCOS) and/or oligo-anovulation. Further, obstetric and perinatal risks in HRT FET are summarized. RECENT FINDINGS: The presence of a corpus luteum seems to reduce the risk of pregnancy-related hypertension and preeclampsia after FET. As a natural cycle (NC) FET is not an option for women with oligo-/amenorrhea these women may benefit from FET with mild stimulation compared to HRT FET. The intention of mild stimulation in anovulatory women is to induce (mono) ovulation to mimic the endocrine profiles of the natural cycle and the early pregnancy after natural conception. Mild stimulation by letrozole is patient friendly and cheap compared to gonadotropin stimulated FET and has been increasingly used in recent years. Although the quality of evidence is low, the pregnancy outcomes after letrozole FET seems similar or even better compared to HRT FET in women with PCOS and/or oligo-anovulation. SUMMARY: Natural and modified NC FET should be used whenever possible to mitigate adverse obstetric and perinatal outcomes after HRT FET. For anovulatory women, whenever ovulation can be induced, we advocate the use of mild stimulation FET to create a corpus luteum awaiting results from RCTs limited to oligo-anovulatory women.

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.

Preimplantation genetic testing in two Danish couples affected by Peutz-Jeghers syndrome.

BACKGROUND: Guidelines from the European Hereditary Tumor Group as well as The Danish National Guidelines for Peutz-Jeghers Syndrome (PJS) state that both prenatal diagnosis and preimplantation genetic testing for monogenic disorders (PGT-M) should be offered to patients with PJS. However, only a few cases resulting in viable pregnancies have been published. OBJECTIVE: We present two cases of PJS patients going through PGT-M for PJS. We highlight the awareness of this possibility and discuss the technical and ethical challenges of performing PGT-M for PJS. METHODS AND RESULTS: Case 1: A 36-year-old male with PJS and his partner were referred for genetic counseling. The patient carried a pathogenic de novo variant in STK11. After a terminated pregnancy of a fetus carrying the same pathogenic variant, microsatellite polymorphic marker analysis was established, and the patient was offered PGT-M. The female partner of the patient gave birth to a healthy boy after five years of fertility treatment. Case 2: A 35-year-old female with PJS and her partner were referred for genetic counseling. She carried an inherited pathogenic STK11 variant. The couple was offered PGT-M. Genetic testing of the embryos was performed using microsatellite polymorphic markers. After two rounds of oocyte extraction a blastocyst predicted not to be affected by PJS was identified. The blastocyst was transferred; however, this did not result in a viable pregnancy. CONCLUSIONS: PGT-M can be offered to patients with PJS. The process may be long and filled with ethical dilemmas requiring patients to be motivated and persistent.

A qualitative study on couples' attitudes and concerns regarding a freeze all strategy in ART treatment.

The freeze all strategy has become a promising alternative to fresh embryo transfer in fertility treatment almost eliminating late ovarian hyperstimulation syndrome (OHSS) in the segmented cycle. There is a lack of in-depth knowledge regarding patients' attitudes towards the freeze all strategy. The aim of this study was to explore the attitudes towards a freeze all strategy compared with fresh embryo transfer in assisted reproductive technology (ART) treatment among couples in a public health care setting. We conducted semi-structured qualitative interviews with ten couples already participants in a randomised controlled trial (RCT) and undergoing ART treatment. The couple's responses showed five themes: (i) Starting treatment provides needed relief; (ii) Treatment must be provided with humanity; (iii) Provision of information instigates positive attitudes towards treatment; (iv) Fresh treatment - 'The normal way'; and (v) Freeze all treatment - 'The new black'. When thorough information about treatment procedures and safety aspects regarding both the freeze all and fresh embryo transfer strategy is given prior to initiation of treatment, couples feel secure and content, regardless of which treatment strategy is finally applied. This qualitative study found that starting treatment could prompt longed-for relief, as professionals would now 'take over' and assist in meeting the couple's family building goals.

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.

Immediate versus postponed frozen embryo transfer after IVF/ICSI: a systematic review and meta-analysis.

BACKGROUND: In Europe, the number of frozen embryo transfer (FET) cycles is steadily increasing, now accounting for more than 190 000 cycles per year. It is standard clinical practice to postpone FET for at least one menstrual cycle following a failed fresh transfer or after a freeze-all cycle. The purpose of this practice is to minimise the possible residual negative effect of ovarian stimulation on the resumption of a normal ovulatory cycle and receptivity of the endometrium. Although elective deferral of FET may unnecessarily delay time to pregnancy, immediate FET may be inefficient in a clinical setting, following an increased risk of irregular ovulatory cycles and the presence of functional cysts, increasing the risk of cycle cancellation. OBJECTIVE AND RATIONALE: This review explores the impact of timing of FET in the first cycle (immediate FET) versus the second or subsequent cycle (postponed FET) following a failed fresh transfer or a freeze-all cycle on live birth rate (LBR). Secondary endpoints were implantation, pregnancy and clinical pregnancy rates (CPR) as well as miscarriage rate (MR). SEARCH METHODS: We searched PubMed (MEDLINE) and EMBASE databases for MeSH and Emtree terms, as well as text words related to timing of FET, up to March 2020, in English language. There were no limitations regarding year of publication or duration of follow-up. Inclusion criteria were subfertile women aged 18-46 years with any indication for treatment with IVF/ICSI. Studies on oocyte donation were excluded. All original studies were included, except for case reports, study protocols and abstracts only. Covidence, a Cochrane-tool, was used for sorting and screening of literature. Risk of bias was assessed using the Robins-I tool and the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation framework. OUTCOMES: Out of 4124 search results, 15 studies were included in the review. Studies reporting adjusted odds ratios (aOR) for LBR, CPR and MR were included in meta-analyses. All studies (n = 15) were retrospective cohort studies involving a total of 6,304 immediate FET cycles and 13,851 postponed FET cycles including 8,019 matched controls. Twelve studies of very low to moderate quality reported no difference in LBR with immediate versus postponed FET. Two studies of moderate quality reported a statistically significant increase in LBR with immediate FET and one small study of very low quality reported better LBR with postponed FET. Trends in rates of secondary outcomes followed trends in LBR regarding timing of FET. The meta-analyses showed a significant advantage of immediate FET (n =2,076) compared to postponed FET (n =3,833), with a pooled aOR of 1.20 (95% CI 1.01-1.44) for LBR and a pooled aOR of 1.22 (95% CI 1.07-1.39) for CPR. WIDER IMPLICATIONS: The results of this review indicate a slightly higher LBR and CPR in immediate versus postponed FET. Thus, the standard clinical practice of postponing FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle may not be best clinical practice. However, as only retrospective cohort studies were assessed, the presence of selection bias is apparent, and the quality of evidence thus seems low. Randomised controlled trials including data on cancellation rates and reasons for cancellation are highly needed to provide high-grade evidence regarding clinical practice and patient counselling.

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.

Preimplantation Genetic Testing of Multiple Endocrine Neoplasia Type 2A.

Background: When discussing matters of reproduction, the 2015 revised guidelines for the management of medullary thyroid carcinoma recommend that patients diagnosed with multiple endocrine neoplasia type 2A (MEN 2A) are informed about the option of Preimplantation Genetic Testing for Monogenic Disorders (PGT-M). In addition, patients seem to have a genuine interest in reproductive options. However, there are just two reports worldwide of this technology being used for patients with MEN 2A. We here present, in a Danish couple where the man has MEN 2A, the first European family with children born after PGT-M. Objective: To report the results of PGT-M in relation to multiple endocrine neoplasia type 2A with the aim to increase awareness among physicians treating this and other genetic disorders. Methods: A Danish couple was referred to the PGT Center at Copenhagen University Hospital Rigshospitalet and opted for PGT-M after counseling by a clinical geneticist and a fertility doctor. The embryos were diagnosed using microsatellite polymorphic marker close to RET. Results: The couple had two healthy children born in 2017 and 2019 as a result of a total of three ICSI treatments including controlled ovarian stimulation, oocyte retrieval and PGT-M, and a total of six blastocyst transfers. Conclusion: A session with a clinical geneticist covering all reproductive options for patients in early adult life is a relevant part of the clinical management of patients with MEN 2A, and other patients with hereditary cancer predisposition syndromes.

Biological and Clinical Rationale for Androgen Priming in Ovarian Stimulation.

Androgen receptors are expressed by all stages of growing follicles, and follicular fluid androgen levels are positively correlated to granulosa cell androgen receptor and follicle-stimulating hormone (FSH) receptor expression. Thus, androgens may promote follicular growth, accumulation and/or responsiveness to gonadotropins. This is explored therapeutically in the concept of androgen priming, to improve the ovarian response to stimulation in assisted reproduction. Androgen effects may be achieved in two different ways, either directly by providing exogenous androgen or by providing luteinizing hormone (LH) activity [i.e., LH or human chorionic gonadotropin (hCG)] to stimulate local ovarian production of androgen. The androgen concentrations in follicular fluid by far exceed the levels in female circulation and it has recently been shown that there was no correlation between serum testosterone levels and follicular fluid androgen levels. There is some evidence that administration of exogenous dehydroepiandrosterone or testosterone increases live birth rates, but an optimal protocol has not been established and such adjuvant treatment should be considered experimental. Furthermore, studies exploring long-term administration of LH activity, achieving LH levels comparable to those seen in women with polycystic ovary syndrome, are awaited. The aim of the present review is to discuss critically the most suitable approach for androgen priming from a biological and clinical standpoint, and to evaluate current approaches and results obtained in clinical trials.

Surgery, gonadotropin-releasing hormone agonist downregulation and in vitro fertilisation in women with infertility and endometriomas.

INTRODUCTION: Tonsillectomy is one of the most common procedures in the field of ear, nose and throat procedures. In 2012, the annual incidence in Denmark was 129.4 per 100,000 inhabitants. A common complication is post-tonsillectomy haemorrhaging (PTH). The overall PTH rates vary widely among studies ranging from 0.5% to 33%. METHODS: This was a nationwide open-population, retrospective and registry-based cohort study in Danes who underwent tonsillectomy complicated by PTH in hospitals and private otorhinolaryngology (ORL) offices in the period from 1991 to 2012. RESULTS: In the 1991-2012 period, a total of 177,211 tonsillectomies were performed among which 9,221 had a registered PTH (rPTH) (5.2%). The annual incidence rate of rPTH increased from 3% in 1991 to 13% in 2012 (p less-than 0.05). Males aged 20-40 years had a significantly higher risk of rPTH with the highest increase in rPTH incidence rates from 9.0% in 1998 to 16.4% in 2012 (p less-than 0.05). Approx. 12% had a primary rPTH within the first 24 hours; the maximum incidence of rPTH was on day six (14%). CONCLUSIONS: The rate of rPTH increased from 1991 to 2012 in hospitals and in private ORL office settings alike. There was a significantly higher rate of rPTH in the age group of 20-40 years and a significant geographical difference in rPTH. The highest risk of rPTH was observed on the day of surgery and on day six. TRIAL REGISTRATION: The Danish Data Protection Agency (record number 2012-41-0158) approved this study. FUNDING: The Olga Bryde Nielsen Foundation and H. Skouby & E. Skouby's Foundation supported this study financially.

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.

Ovarian reserve markers and endocrine profile during oral contraception: Is there a link between the degree of ovarian suppression and AMH?

The ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) are suppressed in varying degree during the use of combined oral contraceptives (COC). Further, long-term use of COC can mask a condition of premature ovarian insufficiency. A desirable clinical tool that could distinguish true low ovarian reserve markers from COC-induced low levels during use of COC is warranted. The aim of this multicenter study including 235 COC users was to assess whether low age-adjusted AMH levels during COC use were linked to concomitant low levels of LH, FSH, estradiol and androgens - as a potential future tool to differentiate between 'false', COC-induced low AMH levels vs. true low AMH. Study population and methods: In total, 235 COC users from the general population aged 19-40 years were included. AMH, AFC and a reproductive hormonal profile were measured during COC intake. Age-adjusted AMH levels (Z-scores) were calculated from a comparison group of 983 non-users of COC. Differences in hormonal profile were tested between women with low versus high age-adjusted AMH-quartiles based on non-parametric Wilcoxon rank sum tests. The outcomes of interest were levels of gonadotropins, estradiol and androgens according to the four the age-adjusted AMH quartiles to find out if women with low age-adjusted AMH levels had a stronger gonadotropin suppression compared with women with higher age-adjusted AMH levels. Mean age of COC users was 30.2 years (SD 3.8), median AMH 14 pmol/l (inter-quartile range (IQR) 8.7-23)), median AFC 16 (IQR 11-25). We found no significant differences across the age-adjusted AMH quartiles in either the levels of gonadotropins, estrogens or androgens, respectively. Thus, the degree of suppression of FSH, LH, androgens and estradiol are unlikely to be a useful tool to differentiate between false low and true low ovarian reserve markers during COC use. Presently, there seems to be no alternative to withdrawal of the COC and to re-test the ovarian reserve after 2-3 months. Trial registration Trial no. NCT02785809 (www.clinicaltrials.gov).

Soluble urokinase plasminogen activator receptor (suPAR) as a biomarker of early pregnancy location and viability compared with hCG, progesterone and estradiol.

A circulating biomarker of early pregnancy outcome independent of ultrasonography and gestational age is a coveted goal. This study evaluated soluble urokinase plasminogen activator receptor (suPAR), a well-described marker of inflammation and immunological activation, for this purpose, and compared it with established early pregnancy biomarkers of the luteoplacental phase: progesterone, estradiol and hCG. We merged data from two prospective first trimester cohorts to conduct a case-control study comparing these analytes in women who had either a live birth, a miscarriage or an ectopic pregnancy. The ability to predict pregnancy location and viability was assessed by areas under the receiver operating characteristic curves (AUC). Comparing women irrespective of gestational age with a live birth, miscarriage or ectopic pregnancy showed significantly lower suPAR values in the latter group (2.4 vs. 2.4 vs. 2.0 µg/L, p = 0.032, respectively), as were all other analytes. Before 6 weeks' gestation, suPAR was significantly inferior to progesterone, estradiol and hCG in pregnancy location and viability prediction (in 124 pregnancies, suPAR AUClocation = 0.69 [CI: 0.54-0.83] and AUCviability = 0.58 [CI: 0.48-0.69], while progesterone AUClocation = 0.95 [CI: 0.87-1.00] and AUCviability = 0.84 [CI: 0.75-0.92]). After 6 weeks' gestation, suPAR prediction improved but was inferior to hCG, progesterone and estradiol (in 188 pregnanices, suPAR AUClocation = 0.71 [CI: 0.63-0.78] and AUCviability = 0.70 [CI: 0.63-0.78] compared with hCG AUClocation = 0.96 [CI: 0.93-0.99] and AUCviability = 0.96 [CI: 0.93-0.98]). Collectively, suPAR is less useful as a predictor of early pregnancy outcome than hCG, progesterone and estradol.