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Abstract Background In assisted reproductive technology, prediction of treatment failure remains a great challenge. The development of more sensitive assays for measuring anti-Müllerian hormone (AMH) has allowed for the possibility to investigate if a lower threshold of AMH can be established predicting very limited or no response to maximal ovarian stimulation. Methods A prospective observational multicenter study of 107 women,

Abstract Objective Single‐photon emission computed tomography (SPECT) with the tracer 99mTc‐HMPAO is a method to visualize the cerebral hyperperfusion during an epileptic seizure and thus localize the epileptogenic zone and seizure propagation. Subtraction of interictal from Ictal SPECT Co‐registered to MRI (SISCOM) visualizes areas with relative increases in cerebral blood flow. The purpose of this retrospective study is to explore the added value of visualizing areas of hypoperfusion as well as hyperperfusion, so‐called reversed SISCOM. Methods Fifty‐six patients operated for epilepsy who had been investigated with SISCOM were included in the analysis. The patients were divided into two groups based on seizure duration after tracer injection, above or below 30 s. The preoperative SISCOM description was compared to the area of resection and given a concordance score. The 56 SISCOM were recalculated visualizing also areas of hypoperfusion and again compared to the site of resection using the same scale of concordance. The reversed SISCOM were categorized into three subgroups: “Altered Conclusion,” “Confirmed Conclusion,” and “Adds Nothing.” If an area of hyperperfusion had an area of hypoperfusion in close proximity, it was re‐interpreted as noise, thus possibly altering the conclusion. If the areas of hypoperfusion were in the opposite hemisphere it was interpreted as confirming factor. Further the concordance scores from conventional SISCOM and reversed SISCOM was compared to surgical outcome to explore the difference in sensitivity, positive predictive value (PPV), and odds ratio. Results In approximately half of the cases reversed SISCOM added additional value, meaning either altered the conclusion or confirmed the conclusion. The sensitivity, PPV, and odds ratio was also better in the subgroup of long, >30 s seizure duration after injection, and got worse in the group with short,

Abstract Objective This retrospective study investigates the predictive value of ictal subtraction single‐photon emission computed tomography (SPECT) co‐registered to magnetic resonance imaging (MRI) (SISCOM) for successful epilepsy surgery. Methods 57 patients examined with SISCOM as a part of epilepsy surgery evaluation were divided into two groups based on seizure duration after tracer injection (group 1: Seizure duration above or equal to 30 s, group 2: Seizure duration under 30 s). SISCOM was compared to the surgical site and categorized as good or poor concordance. Subsequently, Odds ratios (ORs) and positive predictive values (PPVs) were calculated for each group for good surgical outcome, freedom from disabling seizures. Results The PPVs and ORs for good surgical outcome was 74.1% and 5.71 for group 1 and 40% and 0.22 for group 2. SISCOM had a similar positive predictive value regardless of whether the focus was in the same or neighboring lobe, but same hemisphere as the resection. Conclusion In conclusion, the implementation of a precise definition for a well‐executed ictal SPECT scan with respect to seizure duration after injection enhances the positive predictive value (PPV) and odds ratio (OR) for successful surgical outcome, surpassing previous findings, whether the focus in resected lobe or the neighboring.

Background: A higher risk of placenta previa after assisted reproductive technology (ART) is well established. The underlying mechanisms are poorly understood, but may relate to embryo culture duration, cryopreservation, and cause of infertility. Within-mother analyses, where each woman is her own control (i.e., sibling design), help disentangle treatment contributions from maternal confounders that are stable between pregnancies. We aimed to investigate the risk of placenta previa in pregnancies achieved after ART according to embryo culture duration, cryopreservation, and infertility factors while accounting for stable maternal factors using within-mother analyses. Methods and findings: We used linked nationwide registry data from Denmark (1994 to 2014), Finland (1990 to 2014), Norway (1988 to 2015), and Sweden (1988 to 2015). All women who gave their first birth during the study period at age 20 years or older were eligible and contributed up to 4 deliveries (singleton or multifetal) occurring between 22 and 44 weeks of gestation, excluding deliveries where maternal age exceeded 45 years. We used multilevel logistic regression to compare risk of placenta previa after ART (n = 139,694 deliveries) versus natural conception (n = 5,614,512 deliveries), both at the population level and within mothers, adjusting for year of delivery, maternal age, parity, and country. We categorized ART according to culture duration, embryo cryopreservation, and infertility factors. Population level risk of placenta previa was higher for ART versus natural conception (odds ratio [OR], 4.16; 95% confidence interval [CI], 3.96–4.37). Controlling for stable maternal factors, the association attenuated, but risk remained higher for ART versus natural conception (OR within mothers, 2.64; 95% CI, 2.31–3.02). Compared to naturally conceived, a larger difference in risk was seen for pregnancies from fresh embryos than for pregnancies from frozen embryos. Further categorization by culture duration showed the largest risk difference after fresh blastocyst transfer, and the smallest after frozen cleavage stage embryo transfer, which persisted in sensitivity analyses (including restriction to singletons). When stratified according to infertility factors at the population level, women with endometriosis conceiving by ART had the highest risk of placenta previa (OR, 9.35; 95% CI, 8.50–10.29), whereas women with polycystic ovary syndrome (PCOS) conceiving by ART had the lowest risk (OR, 1.52; 95% CI, 1.12–2.09), compared to natural conception. Within mothers, we found a higher risk of placenta previa after ART compared to natural conception for women with endometriosis (OR, 2.08; 95% CI, 1.50–2.90), but not for women with PCOS (OR, 0.88; 95% CI, 0.41–1.89 [unadjusted due to sparse data]). However, within-mother analyses are restricted to multiparous women with deliveries after different conception methods. Therefore, findings from these analyses might not generalize to all women undergoing ART. Conclusions: The risk of placenta previa in pregnancies conceived by ART differed by embryo culture duration, cryopreservation, and underlying infertility. The highest risk was seen after fresh embryo transfer and especially fresh blastocyst transfer. Women with endometriosis had a higher risk than women with other infertility factors, and within mothers, their risk was higher after ART than after natural conception. Identifying the responsible mechanisms might provide opportunities for prevention. Erik Landsverk and colleagues investigate the mechanisms associated with the elevated risk of placenta previa after assisted reproductive technology, while controlling for maternal confounders by using a sibling design. Author summary: Why was this study done?: Studies indicate risk of placenta previa in assisted reproductive technology (ART) differs by type of ART method and underlying infertility. We aimed to increase our understanding of these factors' contributions by improved confounding control using within-mother (sibling) analyses. What did the researchers do and find?: Using each mother as her own control, we found the highest risk of placenta previa after fresh blastocyst transfer. In addition, we found a markedly higher risk among women with endometriosis who conceived after assisted reproductive technology, which remained doubled compared to natural conception after controlling for maternal factors through within-mother analyses. What do these findings mean?: This study strengthens evidence that treatment and maternal factors may both contribute to risk of placenta previa in assisted reproductive technology. Further insights into the mechanisms responsible might lead to development of safer ART methods. Although within-mother analyses are less prone to confounding from stable maternal factors, the findings of these analyses require that women have several births; hence, results might not apply to all women using ART. [ABSTRACT FROM AUTHOR]

STUDY QUESTION To what extent can hypertensive disorders in pregnancy (HDP) explain the higher risk of preterm birth following frozen embryo transfer (frozen-ET) and fresh embryo transfer (fresh-ET) in ART compared with naturally conceived pregnancies? SUMMARY ANSWER HDP did not contribute to the higher risk of preterm birth in pregnancies after fresh-ET but mediated 20.7% of the association between frozen-ET and preterm birth. WHAT IS KNOWN ALREADY Risk of preterm birth is higher after ART compared to natural conception. However, there is also a higher risk of HDP in pregnancies after ART compared to natural conception, in particular after frozen-ET. HDP increases the risk of both spontaneous and medically indicated preterm birth. It is not known to what extent the higher risk of preterm birth in ART-conceived pregnancies is mediated through HDP. STUDY DESIGN, SIZE, DURATION This registry-based cohort study included singleton pregnancies from the Committee of Nordic ART and Safety (CoNARTaS) cohort from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015). The analysis included 78 300 singletons born after fresh-ET, 18 037 after frozen-ET, and 4 426 682 after natural conception. The exposure was ART conception with either frozen-ET or fresh-ET versus natural conception. The main mediator of interest was any of the following HDP: gestational hypertension, preeclampsia, eclampsia, or chronic hypertension with superimposed preeclampsia. The main outcome was any preterm birth, defined as delivery <37 weeks of gestation. Secondary outcomes were spontaneous and medically indicated preterm birth, and different severities of preterm birth based on the gestational age threshold. PARTICIPANTS/MATERIALS, SETTING, METHODS We linked data from the national Medical Birth Registries, ART registries/databases, and the National Patient Registries in each country using the unique national identity number of the mother. Criteria for inclusion were singleton pregnancies with birth order 1–4 in women aged ≥20 years at delivery. We used logistic regression to estimate odds ratios (ORs) with 95% CIs of preterm birth and decomposed the total effect into direct and mediated (indirect) effects to estimate the proportion mediated by HDP. Main models included adjustment for the year of delivery, maternal age, parity, and country. MAIN RESULTS AND THE ROLE OF CHANCE Pregnancies following frozen-ET had a higher risk of any preterm birth compared to natural conception (occurrence 6.6% vs 5.0%, total effect OR 1.29, 95% CI 1.21–1.37) and 20.7% of the association was mediated by HDP (mediated effect OR 1.05, 95% CI 1.04–1.05). The mediation occurred primarily in medically indicated preterm births. Pregnancies following fresh-ET also had a higher risk of any preterm birth compared to naturally conceived pregnancies (occurrence 8.1% vs 5.0%, total effect OR 1.49, 95% CI: 1.45–1.53), but none of this could be mediated by HDP (mediated effect OR 1.00, 95%CI 1.00–1.00, proportion mediated 0.5%). Sensitivity analyses with extra confounder adjustment for body mass index and smoking, and restriction to primiparous women, were consistent with our main findings. Furthermore, the results were not driven by differences in ART procedures (intracytoplasmic sperm injection, culture duration, or the number of embryos transferred). LIMITATIONS, REASONS FOR CAUTION Although we could adjust for some important confounders, we cannot exclude residual confounding, particularly from factors associated with infertility. WIDER IMPLICATIONS OF THE FINDINGS This population-based mediation analysis suggests that some of the higher risk of preterm birth after ART treatment may be explained by the higher risk of HDP after frozen-ET. If causality is established, investigations into preventive strategies such as prophylactic aspirin in pregnancies after frozen-ET may be warranted. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by NordForsk (project number: 71450), the Nordic Federation of Obstetrics and Gynaecology (project numbers NF13041, NF15058, NF16026, and NF17043), the Norwegian University of Science and Technology (project number 81850092), an ESHRE Grant for research in reproductive medicine (grant number 2022-2), and the Research Council of Norway's Centres of Excellence funding scheme (project number 262700). D.A.L.'s and A.E.'s contribution to this work was supported by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreements No 101021566) and the UK Medical Research Council (MC_UU_00032/05). D.A.L. has received support from Roche Diagnostics and Medtronic Ltd for research unrelated to that presented here. Pinborg declares grants from Gedeon Richter, Ferring, Cryos, and Merck, consulting fees from IBSA, Ferring, Gedeon Richter, Cryos, and Merck, payments from Gedeon Richter, Ferring, Merck, and Organon,travel support from Gedeon Richter. All other authors declare no conflicts of interest related to this work. TRIAL REGISTRATION NUMBER ISRCTN 35879. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are there differences in psychosocial and physical wellbeing among women and male partners undergoing modified natural cycle (mNC) frozen embryo transfer (FET) in immediate compared to postponed cycles after ovarian stimulation (OS) and oocyte pick-up (OPU)? SUMMARY ANSWER Significantly more women in the immediate group reported physical symptoms than women in the postponed group whilst fewer were emotionally affected by waiting time, although the latter difference lost statistical significance after adjustment for multiple testing. WHAT IS KNOWN ALREADY Infertility and fertility treatment are known to cause psychosocial distress in women and couples longing for a child. The treatment may be long-term and delayed for various reasons, such as the elective postponement of FET after a fresh transfer without pregnancy or an elective freeze-all cycle, possibly further increasing the level of distress. STUDY DESIGN, SIZE, DURATION Sub-study of an ongoing multicentre randomized controlled, non-inferiority trial assessing the optimal timing for mNC-FET treatment after OS and OPU. Participants were randomized 1:1 to mNC-FET in the cycle immediately following OS or mNC-FET in a subsequent cycle. The study is based on data from the first women (N = 300) and male partners (N = 228) invited to answer a self-reported questionnaire assessing psychosocial and physical wellbeing. Data were collected from April 2021 to March 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS Questionnaires were distributed to all randomized women and their male partners on cycle day 2–5 of mNC-FET cycles and returned before the administration of ovulation trigger. The questionnaire consisted of validated items originating from the Copenhagen Multicentre Psychosocial Infertility—Fertility Problem Stress Scale (COMPI-FPSS) and Marital Benefit Measure (COMPI-MBM). Emotional reactions to waiting time in fertility treatment, mental health, general quality-of-life, and physical symptoms were also assessed. MAIN RESULTS AND THE ROLE OF CHANCE Questionnaire response rates were 90.3% for women and 80.0% for male partners in the immediate group, and 82.3% for women and 57.3% for male partners in the postponed group. Approximately 90% of all women worried to some or a great extent about whether the treatment would be successful. More women in the postponed group reported that they were emotionally affected by the waiting time from OPU to blastocyst transfer to some or to a great extent (57.4% versus 73.9% in the immediate versus postponed group, P  = 0.014), but the results were not significant after adjustment for multiple testing (P  = 0.125). For male partners, no difference in emotional reactions to waiting time between groups was found. There was no significant difference in total infertility-related stress or symptoms of severe depression between the immediate and the postponed group for women or male partners, but women were generally more distressed than their partners. There was a significantly higher incidence of stomach and/or pelvic pain (24.0% versus 9.4%, adjusted P  = 0.013), feeling of being bloated (33.8% versus 15.1%, adjusted P  = 0.010) and swollen or tender breasts (24.8% versus 0.9%, P  < 0.001) in the immediate group. LIMITATIONS, REASONS FOR CAUTION All items were self-reported. No assessment of psychosocial or physical wellbeing was performed before participant enrolment. The sample size of male partners was relatively small, and female partners were not included in this sub-study due to a very small number of participants in this group. WIDER IMPLICATIONS OF THE FINDINGS If immediate mNC-FET proves to be effective, physical and emotional factors may play a key role in choosing treatment strategy for the individual patient. This study demonstrated more physical symptoms related to OS in the immediate cycles. STUDY FUNDING/COMPETING INTEREST(S) The RCT was supported by Rigshospitalet's Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos as payment to the institution. A.P. received consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, and honoraria from Organon, Ferring Pharmaceuticals, Gedeon Richter and Merck A/S. A.P. received support for meeting attendance from Gedeon Richter. M.S. benefitted from a grant from Gedeon Richter. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. N.C.F. received grants from Gedeon Richter, Merck A/S and Cryos as payment to the institution. N.C.F. received consulting fees from Merck A/S and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. E.L. received a radiometer contract on blood gas validation as a payment to the institution. E.L. received honoraria from Pfizer and support for meeting attendance from Astella. B.N. received grants from IBSA, Ferring Pharmaceuticals, Merck A/S, and Gedeon Richter as payment to the institution. B.N. received honoraria from Merck A/S and Organon and support for meeting attendance from IBSA and Gedeon Richter. B.N. and L.P. participate in an Advisory Board at Ferring Pharmaceuticals. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT04748874 [ABSTRACT FROM AUTHOR]

Background and Aims Children born after assisted reproductive technology (ART) have worse perinatal outcomes compared with spontaneously conceived children. This study investigates whether children conceived after ART have a higher risk of congenital heart defects (CHDs) compared with children born after spontaneous conception (SC). Methods All 7 747 637 liveborn children in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015), and Sweden (1987–2015), where 171 735 children were conceived after ART, were included. National ART and medical birth registry data were cross-linked with data from other health and population registries. Outcomes were major CHDs, severe CHDs, 6 hierarchical CHD lesion groups, and 10 selected major CHDs, diagnosed prenatally or up to 1 year of age (Denmark, Finland, and Sweden) and prenatally or at birth (Norway). The association between ART and CHDs was assessed with multivariable logistic regression analysis, with adjustment for available confounders. Results Major CHDs were detected in 3159 children born after ART (1.84%) and in 86 824 children born after SC [1.15%; adjusted odds ratio (AOR) 1.36; 95% confidence interval (CI) 1.31–1.41]. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 594 children born after ART (0.35%) and in 19 375 children born after SC (0.26%; AOR 1.30; 95% CI 1.20–1.42). Risk was similar between ICSI and IVF and between frozen and fresh embryo transfer. Conclusions Assisted reproductive technology–conceived children have a higher prevalence of major CHDs, being rare, but severe conditions. The absolute risks are, however, modest and partly associated with multiple pregnancies, more prevalent in ART. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Synaptic vesicle glycoprotein-2 (SV2) is a family of proteins consisting of SV2A, SV2B, and SV2C. This protein family has attracted attention in recent years after SV2A was shown to be an epileptic drug target and a perhaps a biomarker of synaptic density. So far, the anatomical localization of these proteins in the rodent and human brain have been reported, but co-expression of SV2 genes on a cellular level, their expressions in the human brain, comparison to radioligand binding, any possible regulation in epilepsy are not known. We have here analyzed the expression of SV2 genes in neuronal subtypes in the temporal neocortex in selected specimens by using single nucleus-RNA sequencing, and performed quantitative PCR in populations of temporal lobe epilepsy (TLE) patients and healthy controls. [3H]-UCB-J autoradiography was performed to analyze the correlation between the mRNA transcript and binding capacity to SV2A. Our data showed that the SV2A transcript is expressed in all glutamatergic and GABAergic cortical subtypes, while SV2B expression is restricted to only the glutamatergic neurons and SV2C has very limited expression in a small subgroup of GABAergic interneurons. The level of [3H]-UCB-J binding and the concentration of SV2A mRNA is strongly correlated in each patient, and the expression is lower in the TLE patients. There is no relationship between SV2A expression and age, sex, seizure frequency, duration of epilepsy, or whether patients were recently treated with levetiracetam or not. Collectively, these findings point out a neuronal subtype-specific distribution of the expression of the three SV2 genes, and the lower levels of both radioligand binding and expression further emphasize the significance of these proteins in this disease.