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Background: In conventional, gonadotropin stimulated, in vitro fertilization or intracytoplasmic sperm injection (c-IVF/ICSI) growth and development of multiple follicles is induced by gonadotropins, combined with gonadotropin-releasing hormone agonist or antagonist. In recent studies, singletons conceived after c-IVF/ICSI cycles had lower birth weight not only than spontaneously conceived children but also children born after unstimulated natural IVF/ICSI cycles (NC-IVF/ICSI). Lower birth weight is associated with a catch-up growth within the first years of life. Following the Barker hypothesis accelerated growth has been associated with a higher risk of cardiovascular diseases later in life. The aim of the study is to assess, if children conceived with NC-IVF/ICSI have a higher birthweight and therefore do not show a catch-up growth within the first two years. Therefore, we assume that children born after NC-IVF/ICSI have a better long-term cardiometabolic risk profile. Whether the weight- and height gain is comparable to spontaneously conceived children is unknown, since to our knowledge we are the first study to investigate the longitudinal growth of children born after unstimulated natural cycle ICSI (NC-ICSI)., Material and Methods: We conducted a single-center, prospective cohort study (2010-2017) including children ( n  = 139) born after NC-ICSI or c-ICSI treatment. Growth parameters up to 24 months were collected. Standard deviation scores based on growth references were calculated., Results: The study included 98 children in the NC-ICSI and 41 children in the c-ICSI group. The median birth weight in NC-ICSI children was 3.4 kg [0.1 standard deviation score (SDS)] compared to 3.3 kg (-0.3 SDS) in c-ICSI children ( p  = 0.61). Median length at birth was 50 cm in both groups (NC-ICSI (-0.5 SDS), c-ICSI children (-0.8 SDS), p  = 0.48). At age 24 months, median weight in NC-ICSI children was 12.2 kg (0.3 SDS) versus 12.2 kg (0.2 SDS) in c-ICSI children ( p  = 0.82) and median length 87.5 cm (0.1 SDS) versus 88.0 cm (0.4 SDS) ( p  = 0.43)., Conclusion: We found no difference in growth between children conceived after stimulated and unstimulated ICSI. Growth parameters of both treatment groups did not differ from Swiss national growth references ( N  = 8500). One of the main limitations of our study was the small sample size ( N  = 139) of complete data sets over time and the high drop-out rate of 49% (68/139). Nevertheless, with the increasing number of children born after IVF/ICSI every year it is of immense importance to search for possibilities to reduce their long-term cardiometabolic risk and we want our data to contribute to this discussion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Minger, Sommer, Mitter, Purtschert, von Wolff and Kohl Schwartz.)

Objective:  The effect of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. We aimed to explore the effect of alirocumab added to high-intensity statin therapy on P2Y12 reaction unit (PRU) among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). In addition, we assessed circulating platelet-derived noncoding RNAs (microRNAs and YRNAs)., Methods:  This was a prespecified, powered, pharmacodynamic substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Patients recruited at Bern University Hospital, receiving DAPT with a potent P2Y12 inhibitor, and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The primary endpoint was PRU at 4 weeks after study drug initiation as assessed by VerifyNow P2Y12 point-of-care assays., Results:  Among 139 randomized patients, the majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] in the alirocumab group vs. 69 [94.5%] in the placebo group, p  = 0.14). There were no significant differences in the primary endpoint PRU at 4 weeks between groups (12.5 [interquartile range, IQR: 27.0] vs. 19.0 [IQR: 30.0], p  = 0.26). Consistent results were observed in 126 patients treated with ticagrelor (13.0 [IQR: 20.0] vs. 18.0 [IQR: 27.0], p  = 0.28). Similarly, platelet-derived noncoding RNAs did not significantly differ between groups., Conclusion:  Among AMI patients receiving DAPT with a potent P2Y12 inhibitor, alirocumab had no significant effect on platelet reactivity as assessed by PRU and platelet-derived noncoding RNAs., Competing Interests: Y.U. reports personal fees from Infraredx outside the submitted work. S.L. is employed by CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. D.S. reports receiving personal fees from Sanofi-Aventis (Suisse) outside the submitted work. S.S. reports research grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott, and personal fees from Boston Scientific, Teleflex, and BTG. M.V. reports research grants to the institution from Terumo and Concept Medical and consulting fees from AstraZeneca, Terumo, Alvimedica/CID, Abiomed, Amgen, Abbott Vascular, Daiichi Sankyo, Bayer, CoreFLOW, DORSIA PHARMACEUTICALS LTD, Universität Basel Dept. Klinische Forschung, Vifor, Bristol Myers Squib SA, Biotronik, Boston Scientific, Medtronic, Vesalio, Novartis, Chiesi, PhaseBio, and ECRI, outside the submitted work. S.W. reports research and educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, and V-Wave. S.W. serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. M.M. is a British Heart Foundation (BHF) Chair Holder (CH/16/3/32406) with BHF program grant support (RG/F/21/110053). He is also supported by the Leducq Foundation (18CVD02) and VASCage-C (Research Centre on Vascular Aging and Stroke), an R&D K-Centre of the Austrian Research Promotion Agency (COMET program—Competence Centres for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs, and the federal states Tyrol, Salzburg, and Vienna with the grant number FSG 868624. He has filed and licensed patents on microRNAs as biomarkers. L.R. received a grant to the institution for the conduction of the PACMAN AMI study by Sanofi, Regeneron, and Infraredx. L.R. received research grants to the institution by Abbott, Boston Scientific, Biotronik, and Heartflow, and speaker or consultation fees by Abbott, Amgen, AstraZeneca, Canon, Novo Nordisk, Medtronic, Occlutech, and Sanofi., (Thieme. All rights reserved.)

Purpose: To examine the association between endometriosis and adverse pregnancy and perinatal outcomes (preeclampsia, placenta previa, and preterm birth)., Methods: A population-based retrospective cohort study was conducted among 468,778 eligible women who contributed 912,747 singleton livebirths between 1980 and 2015 in Western Australia (WA). We used probabilistically linked perinatal and hospital separation data from the WA data linkage system's Midwives Notification System and Hospital Morbidity Data Collection databases. We used a doubly robust estimator by combining the inverse probability weighting with the outcome regression model to estimate adjusted risk ratios (RR) and 95% confidence intervals (CIs)., Results: There were 19,476 singleton livebirths among 8874 women diagnosed with endometriosis. Using a doubly robust estimator, we found pregnancies in women with endometriosis to be associated with an increased risk of preeclampsia with RR of 1.18, 95% CI 1.11-1.26, placenta previa (RR 1.59, 95% CI 1.42-1.79) and preterm birth (RR 1.45, 95% CI 1.37-1.54). The observed association persisted after stratified by the use of Medically Assisted Reproduction, with a slightly elevated risk among pregnancies conceived spontaneously., Conclusions: In this large population-based cohort, endometriosis is associated with an increased risk of preeclampsia, placenta previa, and preterm birth, independent of the use of Medically Assisted Reproduction. This may help to enhance future obstetric care among this population., (© 2023. The Author(s).)

Background: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care., Methods: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified., Results: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care., Conclusions: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MHB reports receiving fees paid to her institution by valproate market authorization holders for EMA-mandated contract research; speaking and/or advisory board honoraria from Eisai, Novartis Norway, Jazz Pharmaceuticals, Angelini Pharma, Teva, Lilly, and Lundbeck; the other authors do not declare any conflict of interest.

Background: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls)., Methods: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10 -8 , not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis., Results: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs., Conclusions: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration., (© 2023. The Author(s).)

Introduction: The COVID-19 pandemic forced people to give up their daily routines and adjust to new circumstances. This might have affected health-related quality of life (HRQOL). We aimed to compare HRQOL during the first COVID-19 wave in 2020 to HRQOL before the pandemic and to identify determinants of HRQOL during the pandemic in Switzerland., Methods: We conducted a cross-sectional online survey during the pandemic (between May and July 2020; CoWELL sample; convenience sample). Before the pandemic (2015-2016), we had conducted a cross-sectional paper-based survey among a representative random sample of the Swiss general population (SGP sample). In both samples, we assessed physical and mental HRQOL (Short Form-36) and socio-demographic characteristics. In the CoWELL sample, we additionally assessed health- and COVID-19-related characteristics. Data were analysed using linear regressions., Results: The CoWELL sample included 1581 participants (76% women; mean age = 43 years, SD = 14 years) and the SGP sample 1209 participants (58% women, mean age = 49 years, SD = 15 years). Adjusted for sex, age, and education, the CoWELL sample reported higher physical HRQOL (PCS, +5.8 (95% CI: 5.1, 6.6), p < 0.001) and lower mental HRQOL (MCS, -6.9 (-7.8, -6.0), p < 0.001) than the SGP sample. In the CoWELL sample, especially persons with lower health literacy, who had no support network or who have had COVID-19, reported lower HRQOL., Discussion: Aspects unique to the COVID-19 pandemic affected HRQOL. Vulnerable persons such as those having had COVID-19, less support opportunities, and with lower health literacy are especially prone to impaired HRQOL during the COVID-19 pandemic., (© 2023. The Author(s).)

Research Question: Does antioestrogen effect of clomiphene citrate (CC) on the endometrium reduce implantation and thereby decrease pregnancy and live birth rate per transferred embryo?, Methods: In this cohort, unstimulated IVF cycles modified with clomiphene citrate (CC-NC-IVF) and unstimulated, natural IVF cycles (NC-IVF) conducted between 2011 and 2016 were included. CC was applied in a dosage of 25mcg per day, starting on cycle day 7 until ovulation trigger day. Primary outcomes were clinical pregnancy rate, defined as amniotic sac visible in ultrasound, and live birth rate per transferred embryo. Miscarriage rate calculated as amniotic sac not ending in a live birth was secondary outcome. A modified mixed-effect Poisson regression model was applied, and adjustments were made for female age, parity, type and cause of infertility. Additionally, stratification by parity and age was performed., Results: Four hundred and ninety-nine couples underwent a total of 1042 IVF cycles, 453 being NC-IVF and 589 being CC-NC-IVF cycles. Baseline characteristics of both groups did not differ. Addition of CC did neither decrease clinical pregnancy rate (aRR 0.86; 95% CI 0.67-1.12) nor live birth rate per transferred embryo (aRR 0.84; 95% CI 0.62-1.13) in comparison with NC-IVF. Miscarriage rate did not differ between CC-NC-IVF and NC-IVF (aRR 0.95; 95% CI 0.57-1.57)., Conclusion: Low-dose CC does not reduce pregnancy or live birth rate per transferred embryo. It can be used in infertility treatment without negatively affecting the endometrium and implantation., (© 2022. The Author(s).)

Research suggests that gonadotropin stimulation in in vitro fertilization (IVF) treatment affects embryo quality and the endometrium that might influence embryo implantation, placentation and establishment of a viable pregnancy. We assessed the impact of gonadotropin stimulation on implantation, live birth and miscarriage rates per transferred embryo by comparing stimulated and unstimulated IVF treatment. In a cohort of 728 couples, 1310 IVF cycles with successful embryo transfer were analysed; 857 cycles were stimulated with gonadotropins > 75 IU/day (333 poor responder < 4 oocytes; 524 normal responders), and 453 were unstimulated. In total, 1913 fresh cleavage-stage embryos were transferred. Zygote but no embryo selection was performed, and supernumerous zygotes were vitrified. The implantation rate was defined as number of sonographically detected amniotic sacs; live birth rate as number of children born per transferred embryo. Modified mixed effect Poisson regression was used to account for the dependency of cycles and embryos within the same women and the same transfer cycle. Adjustments were made for maternal age, parity, primary or secondary infertility and indication for IVF. Per transferred embryo, implantation rates (rate ratio (RR) 1.37; 95% CI 1.04-1.81; p = 0.028; aRR 1.42; 95% CI 1.10-1.84; p = 0.008) and live birth rates (RR 1.33; 95% CI 0.95-1.86; p = 0.093; aRR 1.38; 95% CI 1.01-1.88; p = 0.044) were higher in NC-IVF compared to cIVF normal responders. Miscarriage did not differ (RR 0.99; 95% CI 0.59-1.65; p = 0.965; aRR 0.90; 95% CI 0.52-1.53 p = 0.698). Similar results were obtained in poor responders. The study suggests an impact of gonadotropin stimulation on the implantation potential of embryos., (© 2022. The Author(s).)

Study Question: Are children conceived by ART or born to subfertile parents more susceptible to upper or lower respiratory tract infections (URTI, LRTI)?, Summary Answer: ART-conceived children had a higher frequency of and risk of hospitalization for respiratory infections up to age 3, which was only partly explained by parental subfertility., What Is Known Already: Some studies report increased risks of infections in children conceived by ART. Results for URTIs and LRTIs are inconclusive, and the contribution of underlying parental subfertility remains unclear., Study Design, Size, Duration: We included 84 102 singletons of the Norwegian Mother, Father and Child Cohort Study (MoBa) born between 1999 and 2009. Mothers reported time-to-pregnancy at recruitment and child history of, frequency of and hospitalization for, respiratory infections when the child was 6, 18 and 36 months old by questionnaires. Subfertility was defined as having taken 12 or more months to conceive. The Medical Birth Registry of Norway (MBRN) provided information on ART. URTI included throat and ear infections, while LRTI included bronchitis, bronchiolitis, respiratory syncytial virus and pneumonia., Participants/materials, Setting, Methods: We used log-binomial regression to estimate risk ratios (RR) and 95% CI of any respiratory tract infection and hospitalization, and negative-binomial regression to calculate incidence rate ratios (IRR) and 95% CI for number of infections. We compared children conceived by ART, and naturally conceived children of subfertile parents, to children of fertile parents (<12 months to conceive) while adjusting for maternal age, education, BMI and smoking during pregnancy and previous livebirths. We accounted for dependency between children born to the same mother., Main Results and the Role of Chance: A total of 7334 (8.7%) singletons were naturally conceived by subfertile parents and 1901 (2.3%) were conceived by ART. Between age 0 and 36 months, 41 609 (49.5%) of children experienced any URTI, 15 542 (18.5%) any LRTI and 4134 (4.9%) were hospitalized due to LRTI. Up to age 3, children conceived by ART had higher frequencies of URTI (adjusted IRR (aIRR) 1.16; 95% CI 1.05-1.28) and hospitalizations due to LRTI (adjusted RR (aRR) 1.25; 95% CI 1.02-1.53), which was not seen for children of subfertile parents. Children conceived by ART were not at higher risks of respiratory infections up to age 18 months; only at age 19-36 months, they had increased risk of any LRTI (aRR 1.16; 95% CI 1.01-1.33), increased frequency of LRTIs (IRR 1.22; 95% CI 1.02-1.47) and a higher risk of hospitalization for LRTI (aRR 1.35; 95% CI 1.01-1.80). They also had an increased frequency of URTIs (aIRR; 1.19; 95% CI 1.07-1.33). Children of subfertile parents only had a higher risk of LRTIs (aRR 1.09; 95% CI 1.01-1.17) at age 19-36 months., Limitations, Reasons for Caution: Self-reported time-to-pregnancy and respiratory tract infections by parents could lead to misclassification. Both the initial participation rate and loss to follow up in the MoBa limits generalizability to the general Norwegian population., Wider Implications of the Findings: ART-conceived children might be more susceptible to respiratory tract infections in early childhood. This appears to be only partly explained by underlying parental subfertility. Exactly what aspects related to the ART procedure might be reflected in these associations need to be further investigated., Study Funding/competing Interest(s): Funding was received from the Swiss National Science Foundation (P2BEP3&#95;191798), the Research Council of Norway (no. 262700), and the European Research Council (no. 947684). All authors declare no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Objectives: To describe COVID-19 information-seeking behavior (CISB) during the first stage of the pandemic in Switzerland and identify its determinants. Methods: We conducted an online cross-sectional survey (4 May to 6 July 2020). Participants self-reported their CISB (information sources and frequency), personal COVID-19 situation (e.g., perception about having had COVID-19), sociodemographic information, and completed validated measures of health literacy, and worry and anxiety. Data were analyzed using descriptive statistics and logistic regressions. Results: We included 1,505 participants (24.7% male; mean age = 43.0 years, SD = 13.9). Most participants reported searching for information daily ( n = 1,023, 68.0%) and referring to multiple information sources (mean 3.7, SD = 1.5). Commonly used sources were official websites ( n = 1,129, 75.0%) and newspapers ( n = 997, 66.2%). Participants with higher health literacy were more likely to seek information daily and use online resources, but less likely to use personal networks than those with lower health literacy. We did not find any association between CISB and worry and anxiety. Conclusion: More opportunities for personal dialogue and education about reliable online information resources should be encouraged to optimize the CISB of groups with lower health literacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ilic, Roser, Sommer, Baenziger, Mitter, Mader, Dyntar and Michel.)

Research Question: How are perinatal outcomes of live-born singletons after stimulated and unstimulated IVF different from perinatal outcomes in (i) children born in a tertiary centre and (ii) all children born in Switzerland?, Methods: This cohort study compared the perinatal outcomes of two birth cohorts and the national live birth registry. Relative risks were calculated using modified Poisson regression and clustering for siblings and adjustment for maternal age, parity and childs sex., Results: Of the 636,639 live births, 311 were in the Bern IVF Cohort (144 stimulated, 167 unstimulated), 2332 in the tertiary centre and 633,996 in the Swiss Live Birth Registry (SLBR). Perinatal outcomes following IVF did not differ compared with births in the SLBR (adjusted relative risk [aRR]; 95% confidence interval [CI]), with the exception of the increased risk of small for gestational age (1.31; 1.01 to 1.70, P = 0.04; aRR 1.12; 0.87 to 1.45, P = 0.39). Children born following stimulated IVF had a higher risk of low birthweight (2.17; 1.27 to 3.69, P < 0.01; aRR 1.72; 1.01 to 2.93, P = 0.05), and of being small for gestational age (1.50; 1.05 to 2.14, P = 0.03; aRR 1.31; 0.92 to 1.87; P = 0.13), whereas children born after unstimulated IVF had no increased risks compared with the SLBR. Higher Caesarean rate after IVF was mainly associated with higher maternal age., Conclusion: Singletons in the Bern IVF Cohort do not show less favourable perinatal outcomes. Gonadotrophin stimulation seems to have an effect, because lower risks were associated with unstimulated IVF., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Conducting high quality investigator-initiated trials (IITs) is challenging and costly. The costs of investigational medicinal products (IMPs) in IITs and the role of hospital pharmacies in the planning of IITs are unclear. We conducted a mixed-methods study to compare planned and actual costs of IMPs in Swiss IITs, to examine potential reasons for differences, and to gather stakeholder views about hospital services for IITs., Methods: We included all IITs with IMP services from the Basel hospital pharmacy invoiced between January 2014 and June 2020 (n = 24). We documented trial and IMP characteristics including planned and actual IMP costs. Our working definition for a substantial cost difference was that the actual IMP costs were more than 10% higher than the planned IMP costs in a trial. We conducted semi-structured interviews with investigators, clinical trials unit and hospital pharmacy staff, and qualitatively analyzed transcribed interviews., Results: For 13 IITs we observed no differences between planned and actual costs of IMPs (median, 11'000 US$; interquartile range [IQR], 8'882-16'302 US$), but for 11 IITs we found cost increases from a median of 11'000 US$ (IQR, 8'922-36'166 US$) to a median over 28'000 US$ (IQR, 13'004-49'777 US$). All multicenter trials and 10 of 11 IITs with patients experienced substantial cost differences. From the interviews we identified four main themes: 1) Patient recruitment and organizational problems were identified as main reasons for cost differences, 2) higher actual IMP costs were bearable for most investigators, 3) IMP services for IITs were not a priority for the hospital pharmacy, and 4) closer collaboration between clinical trial unit and hospital pharmacy staff, and sufficient staff for IITs at the hospital pharmacy could improve IMP services., Conclusions: Multicenter IITs enrolling patients are particularly at risk for higher IMP costs than planned. These trials are more difficult to plan and logistically challenging, which leads to delays and expiring IMP shelf-lives. IMP services of hospital pharmacies are important for IITs in Switzerland, but need to be further developed., Competing Interests: The authors have declared that no competing interests exist.

Problem: Repeated implantation failure and recurrent pregnancy loss are associated with chronic endometritis, a persistent endometrial inflammation. Its diagnosis and treatment may increase pregnancy and live birth rates. The aim of this study was to assess the effectiveness of endometrial diagnostic biopsy and subsequent antibiotic treatment in cases of chronic endometritis on reproductive outcomes over a long observation period., Method of Study: We conducted a historical cohort study (2014-2018) at our University-based infertility center that included women (n = 108) with repeated implantation failure or recurrent pregnancy loss without known pathologies associated with either condition. Forty-one women underwent a hysteroscopy only (reference group); the remaining 67 women underwent, in addition to the hysteroscopy, an endometrial diagnostic biopsy with immunohistochemically staining for CD138 to detect plasma cells (biopsy group). If one or more plasma cells were detected, the women were treated with doxycycline 100 mg twice a day orally for 2 weeks. We performed stratified survival analysis (Kaplan-Meier) and Cox regression., Results: The biopsy group had higher chances of pregnancy (hazard ratio 2.28; 95% confidence interval 1.23-4.24; p = .009) and of live birth (hazard ratio 2.76; 95% confidence interval 1.30-5.87; p = .008) compared with the reference group. In the sensitivity analysis, repeated implantation failure or recurrent pregnancy loss did not affect the outcome., Conclusion: Endometrial diagnostic biopsy followed by antibiotic treatment in case of chronic endometritis in women with repeated implantation failure or recurrent pregnancy loss may increase the chances for live birth., (© 2021 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

It is biologically plausible that risk of autism spectrum disorder (ASD) is elevated by both short and long interpregnancy intervals (IPI). We conducted a retrospective cohort study of singleton, non-nulliparous live births, 1998-2007 in Denmark, Finland, and Sweden (N = 925,523 births). Optimal IPI was defined as the IPI at which minimum risk was observed. Generalized additive models were used to estimate relative risks (RR) of ASD and 95% Confidence Intervals (CI). Population impact fractions (PIF) for ASD were estimated under scenarios for shifts in the IPI distribution. We observed that the association between ASD (N = 9302) and IPI was U-shaped for all countries. ASD risk was lowest (optimal IPI) at 35 months for all countries combined, and at 30, 33, and 39 months in Denmark, Finland, and Sweden, respectively. Fully adjusted RRs at IPIs of 6, 12, and 60 months were 1.41 (95% CI: 1.08, 1.85), 1.26 (95% CI: 1.02, 1.56), and 1.24 (95% CI: 0.98, 1.58) compared to an IPI of 35 months. Under the most conservative scenario PIFs ranged from 5% (95% CI: 1%-8%) in Denmark to 9% (95% CI: 6%-12%) in Sweden. The minimum ASD risk followed IPIs of 30-39 months across three countries. These results reflect both direct IPI effects and other, closely related social and biological pathways. If our results reflect biologically causal effects, increasing optimal IPIs and reducing their indications, such as unintended pregnancy and delayed age at first pregnancy has the potential to prevent a salient proportion of ASD cases. LAY SUMMARY: Waiting 35 months to conceive again after giving birth resulted in the least risk of autism. Shorter and longer intervals resulted in risks that were up to 50% and 85% higher, respectively. About 5% to 9% of autism cases might be avoided by optimizing birth spacing., (© 2021 International Society for Autism Research and Wiley Periodicals LLC.)

Research Question: Is the endocrine milieu different in women with low serum anti-Müllerian hormone (AMH) concentration compared with women with high concentration?, Design: Cohort study of 84 women (four groups) classified according to AMH concentration and age undergoing natural cycle IVF treatment. Concentrations of LH, oestradiol, testosterone, androstenedione and AMH were determined in follicular fluid (FF), associations analysed and clinical outcome parameters evaluated., Results: A positive correlation between serum and FF AMH concentrations was confirmed. Follicular fluid androstenedione concentration was positively correlated with serum AMH concentration (P < 0.0001, r 2  = 0.197). The correlation between FF LH and FF testosterone concentration in all women was not significant (P = 0.050, r 2  = 0.046); however, the correlation between FF androstenedione in women with high serum AMH concentration was significant (P = 0.032, r 2  = 0.220). Follicular fluid testosterone and androstenedione were positively correlated with FF oestradiol overall and in some individual groups. The high serum AMH concentration group showed the highest FF AMH and androstenedione concentrations and lowest oestradiol-testosterone and oestradiol-androstenedione ratios. High FF AMH concentration was associated with a higher clinical pregnancy rate and high FF oestradiol concentration with a slightly better embryo quality., Conclusions: Differences in the endocrine milieu in women with high serum AMH concentration seem to be caused by increased follicular LH concentration. In women with high serum AMH concentration, FF androstenedione is increased and ratios of oestradiol-testosterone and oestradiol-androstenedione are decreased, suggesting a disturbed endocrine milieu caused by reduced metabolization of FF androgens into oestrogens. In natural cycles, FF AMH concentrations are positively associated with higher clinical pregnancy rates and oestradiol concentrations with a higher embryo score., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Aim: Breastfeeding has numerous advantages. Our aim was to investigate whether breastfeeding initiation and duration in women with pregnancies conceived through in vitro fertilisation differ from spontaneously conceived pregnancies., Methods: This is a comparative cross-sectional study about breastfeeding behaviour performed at the Bern University Hospital including mothers of singletons conceived by in vitro fertilisation (n = 198) with or without gonadotropin stimulation between 2010 and 2016 (in vitro fertilisation group). They were compared to a population-based control group (n = 1421) of a randomly selected sample of mothers in Switzerland who delivered in 2014., Results: A total of 1619 women were included in this analysis. Breastfeeding initiation rates were high, similar between the in vitro fertilisation group (93.4%) and the control group (94.8%). No increased risk of stopping breastfeeding earlier after in vitro fertilisation treatment compared to the control group could be found over the observational period of 12 months (HR = 1.00, 95% CI 0.83-1.20, P = .984). There was no difference in breastfeeding initiation or duration after gonadotropin-stimulated vs unstimulated in vitro fertilisation., Conclusion: In Switzerland, in vitro fertilisation treatments were not associated with earlier breastfeeding cessation. This result is reassuring for mothers undergoing in vitro fertilisation., (© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim of the Study: The aim was to analyse if ibuprofen, as a non-selective cyclooxygenase (COX) inhibitor, has any negative effect on oocyte competence and embryo quality. COX- inhibitors are popular over-the-counter analgesics. Whereas selective COX inhibitors have been shown to impair female fertility, data on non-selective COX inhibitors are poor. Hence, they have not been recommended for women trying to conceive., Methods: This is an observational study comparing ibuprofen exposed and unexposed women from 18 to 42 years of age, using the model of natural cycle in vitro fertilisation (IVF) to determine oocyte and embryo quality. Follicular growth was monitored and if the follicle was mature (≥ 15mm size and estimated oestradiol level of ≥ 800pmol/l), ovulation was triggered. Women with luteinising hormone (LH) surge received 400mg ibuprofen every 8 hours to postpone ovulation, whereas women without LH surge received none (controls). Oocyte retrieval rate, oocyte maturity, fertilization rate, embryo development and embryo quality as well as implantation rate were analysed., Results: Of the 111 women included, 63 received ibuprofen, and 48 did not. Rates of mature oocytes and implantation rate did not differ. Logistic regression showed no significant association of ibuprofen intake, LH- level or reason for infertility on embryo quality., Conclusion: Based on our results, we suggest that, particularly within natural cycle IVF, ibuprofen does no harm around ovulation as analgesic treatment., Competing Interests: Conflict of Interest statement: The authors have no conflicts of interest to declare., (Copyright © 2020 Facts, Views & Vision.)

Study Question: Does follicular flushing increase the number of mature oocytes in monofollicular IVF?, Summary Answer: Follicular flushing increases the number of mature oocytes in monofollicular IVF., What Is Known Already: Flushing increases neither the oocyte yield nor the pregnancy rate in polyfollicular IVF or in poor responder patients. In monofollicular IVF, the effect of flushing has so far been addressed by two studies: (i) a prospective study with minimal stimulation IVF demonstrated an increased oocyte yield, and (ii) a retrospective study with natural cycle (NC)-IVF showed an increased oocyte yield and an increased transfer rate., Study Design, Size, Duration: Randomized controlled trial including 164 women who were randomized for either aspiration with or without flushing from 2016 to 2019., Participants/materials, Setting, Methods: Infertile women 18-42 years of age with an indication for IVF treatment at a university-based infertility unit. Women undergoing monofollicular IVF were randomized to either follicular aspiration only or follicular aspiration directly followed by five follicular flushes at a 1:1 ratio. The intervention was done without anaesthesia, using a gauge 19 single-lumen needle. Flushing volume was calculated (sphere formula) based on the size of the follicle., Main Results and the Role of Chance: A total of 164 women were included; 81 were allocated to 'aspiration only' and 83 to additional 'flushing'. Primary analysis was based on the intention-to-treat: oocyte yield, defined as the collected mature oocyte rate, was higher (n = 64/83, 77.1%) in the flushing group compared to the aspiration only group (n = 48/81, 59.3%, adjusted risk difference (RD): 18.2% (95% CI 3.9-31.7%), P-value = 0.02). In the flushing group, most oocytes were retrieved within the first three flushes (63/83, 75.8%). Fertilization rate was higher in the flushing group (n = 53/83, 63.9% vs n = 38/81, 46.9%; adjusted RD: 16.8% (96% CI 1.5-31.4%), P = 0.045). Transfer rate was also higher in the flushing group (n = 52/83, 62.7% vs n = 38/81, 46.9%; RD: 15.71 (95% CI 0.3-30.3%)), but the difference was not significant (P = 0.06). The clinical pregnancy rate n = 9/83 versus n = 9/81 (RD: -0.3% (95% CI -9.9% to 9.5%)) and live birth rate n = 7/83 versus n = 8/81 (RD: -1.5% (95% CI -10.4% to 7.1%)) were not significantly different between the flushing and the aspiration group. The median duration of the intervention was significantly longer with flushing (2.38 min; quartiles 2.0, 2.7) versus aspiration only (0.43 min; quartiles 0.3, 0.5) (P < 0.01). There was no significant difference in the mean (±SD) visual analogue scales pain score between the follicular flushing (3.4 ± 1.8) and the aspiration group (3.1 ± 1.89)., Limitations, Reasons for Caution: Blinding of the procedure was not possible., Wider Implications of the Findings: Our study proved that flushing of single follicles in NC-IVF increases the oocyte yield. In contrast to polyfollicular IVF flushing seems to be beneficial in a monofollicular setting if the technique used in our study (single-lumen needle, 5 flushings with flushing volume adaptation) is applied., Study Funding/competing Interest(s): The study was funded by the financial sources of the division and in part by a research grant provided by NMS Biomedical SA, Switzerland. The company did not have any roles in design or conduct of the study or in the preparation of the manuscript. The authors have no other conflicts of interest., Trial Registration Number: Clinicaltrials.gov NCT02641808., Trial Registration Date: 29 December 2015., Date of First Patient’s Enrolment: 22 August 2016., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Aim: To investigate whether the early administration of Euphrasia eye drops® in preterm neonates presenting with ocular discharge fosters the resolution of the ocular discharge and reduces the need for topical antibiotic therapy, as compared to placebo. Methods: We conducted a randomized double-blind placebo-controlled trial at the University Children's Hospital Bern, Switzerland. Preterm neonates with white, yellow, or green ocular discharge were included. Infants were randomly assigned (1:1) to the Euphrasia arm (Euphrasia eye drops®, Weleda AG, Arlesheim) or the placebo arm (NaCl 0.9%). Euphrasia or placebo was administrated at a dose of one drop in each eye four times a day over a period of 96 h. The primary outcome was the treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. Results: A total of 114 neonates were screened and 84 were randomized. Among neonates in the Euphrasia arm, 22 (55.0%) achieved our primary outcome compared to 21 (51.2%) in the placebo arm ( p = 0.85). In the Euphrasia arm, time to resolution of reddening tended to fall within the shorter bracket of 24 to 48 h (24 (92.3%) vs. 12 (80.0%) in the placebo arm, p = 0.34) and relapse or first signs of reddening during the 96-h intervention tended to be lower [3 (7.9%) eyes vs. 8 (18.2%) eyes in the placebo arm, p = 0.17]. Tearing at 96 h tended to be lower in the Euphrasia arm [5 (12.8%) eyes in the Euphrasia arm vs. 12 (27.3%) eyes in the placebo arm, p = 0.10]. Discussion: Euphrasia did not significantly improve treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. However, results suggest that Euphrasia may be of benefit for symptoms such as reddening and tearing, and thus improve the comfort of patients. Trial Registration: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04122300 and at the portal for human research in Switzerland SNCTP000003490., (Copyright © 2020 Meier-Girard, Gerstenberg, Stoffel, Kohler, Klein, Eschenmoser, Mitter, Nelle and Wolf.)

Introduction: Reproductive scientists have postulated various risk factors for lower birthweight following conventional gonadotropin-stimulated in vitro fertilization compared with spontaneously conceived children: parental factors (age, health, duration of subfertility and smoking habits); ovarian stimulation; laboratory procedures; the number of oocytes retrieved and the number of embryos transferred. Our aim was to investigate the impact of gonadotropin stimulation and serum estradiol level on the risk of a newborn being small-for-gestational-age., Material and Methods: We conducted a cohort study (2010-2016) of singletons (n = 155) born either after conventional gonadotropin-stimulated in vitro fertilization (using ≥150 IU/d human gonadotropin for stimulation) or after natural cycle in vitro fertilization without any stimulation. We analyzed perinatal outcomes using birthweight percentiles, adjusted for gestational age and sex., Results: The proportion of small-for-gestational-age was 11.8% following conventional gonadotropin-stimulated in vitro fertilization and 2.9% after natural cycle in vitro fertilization (P = 0.058). The odds of small-for-gestational-age were significantly higher with supraphysiological estradiol levels in maternal serum on ovulation trigger day (unadjusted odds ratio 4.58; 95% confidence interval 1.35-15.55; P = 0.015). It remained significant after adjusting for maternal height, age and body mass index (adjusted odds ratio 3.83; 95% confidence interval 1.06-13.82; P = 0.041)., Conclusions: We found an associated risk of children being born small-for-gestational-age after conventional gonadotropin-stimulated in vitro fertilization compared with natural cycle in vitro fertilization. This higher risk is significantly associated with supraphysiological estradiol levels. We propose a reduction in the dosage of gonadotropin to minimize the risk of small-for-gestational-age and future health consequences., (© 2019 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)