Kristine Løssl

Objective: Infertility is a major health issue, and fertility treatments, including frozen embryo transfer (FET), are common. Progesterone, essential for endometrium development and receptivity, is used to improve implantation rates. This study investigates the effect of luteal phase support with progesterone on thyroid function in modified natural FET cycles. Methods: This is a sub-study of a randomized controlled trial (FET optimizing trial). Data were collected at two fertility centers from January 2019 to October 2022. Euthyroid women receiving single frozen–thawed embryo transfer in a modified natural cycle were included. The study participants were categorized into two groups: the luteal phase support (LPS) and the no LPS groups. The LPS group received vaginal progesterone 100 mg three times daily starting at day 4 after ovulation trigger with human chorionic gonadotropin (day 0). A pregnancy test was performed on day 16. Thyroid function was repeatedly measured. Linear mixed modeling was used to test the effect of progesterone on thyrotropin (TSH, primary outcome) and free thyroxine (fT4). Interaction with thyroid autoimmunity was tested. Results: In total, 85 women were included: 45 received progesterone LPS and 40 did not. Participants were 34 ± 4 years of age and had a BMI of 23 (IQR: 21; 26), and 25% were positive for thyroid autoimmunity. Serum progesterone increased with LPS, but TSH and fT4 levels were not affected by LPS. There was no interaction with thyroid autoimmunity. In the progesterone LPS group, 44% conceived compared with 55% in the no LPS group, P = 0.33. Conclusion: Progesterone LPS does not affect thyroid function during the luteal phase. Trial registration number: This trial was registered with ClinicalTrials.gov (NCT03795220) and EudraCT (2018-002207-34) and was completed.

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. 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. 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. 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.

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.

Introduction: Preimplantation genetic testing (PGT) is growing in importance and volume internationally. International societies such as the European Society for Human Reproduction and Embryology compile international results and these data are published in scientific journals. We present the first compilation of practices, quality measuress and outcome data from Nordic clinics performing PGT.Material and methods: We conducted a structured online survey of PGT practices in the Nordic countries to compare clinical and laboratory techniques, outcomes and quality measures applied in Nordic clinics. The survey was designed by the authors and answered by the authors and members of the study group. The outcome data represents results from 2018. Results and details were clarified through iteration with responding clinics while maintaining anonymity. Response rate in the study was 80%, with 8 of 10 clinics performing PGT responding.Results: Most of the PGT cycles in the Nordic countries are funded through the public healthcare system with University Hospitals performing the majority of treatments, 716/848, or 84.4%, of oocyte retrievals in this dataset. The genetic analyses are in five cases performed by the affiliated local genetic laboratory, and the remaining three consult with large international private enterprise laboratories. Genetic counseling is widely used. Results in the Nordic clinics compare well with international data. Systematic quality control procedures are in place and the larger clinics and laboratories utilize ISO certification or accreditation in the quality management. Automatic witnessing with detailed electronic documentation of laboratory processes is not utilized in the responding clinics, although a majority uses manual witnessing procedures in the laboratory. The outcome after PGT in terms of clinical pregnancy per transfer is around 40% per embryo transfer and compares well with international data.Conclusions: Preimplantation genetic testing is organized in rather few clinics in the Nordic countries and most of them use local laboratories for genetic analyses of the biopsies. Laboratory procedures are largely in accordance with international guidelines and the outcome after PGT in terms of clinical pregnancy per transfer is comparable to results in international reports.

Ovarian reserve can be determined by serum anti‐Müllerian hormone (AMH) level and/or antral follicle count before controlled ovarian stimulation. The aim of controlled ovarian stimulation is to achieve an appropriate number of mature follicles and avoid complications such as ovarian hyperstimulation syndrome. Measurement of the ovarian reserve is useful for clinicians as it predicts the ovarian response to controlled ovarian stimulation. Further, it assists in giving the patient realistic expectations regarding the treatment. By determining the ovarian reserve, the most appropriate stimulation protocol and gonadotropin dose can be chosen specifically for each woman enabling so‐called “individualized treatment” in line with the personalized treatment concept. Many benefits come with using AMH as a biomarker for ovarian reserve; the hormone is considered fairly cycle independent apart from a small decrease in the late follicular phase and there is no inter‐observer variance. However, the use of AMH also has limitations; since the implementation of AMH in fertility treatment several AMH assays have been developed. This has made direct comparisons of AMH serum levels complicated. Currently, no international standardized assays exist. AMH is a valid predictor of the ovarian response to controlled ovarian stimulation and to some extent the chance of pregnancy in relation to assisted reproductive technology, but AMH is less optimal in prediction of spontaneous pregnancy and live birth after assisted reproductive technology. Accordingly, AMH can be used to optimize gonadotropin stimulation in fertility treatment, but is not recommended as a screening tool in the general population.

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.

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”.