Obstetric and perinatal outcomes of women treated for subfertility and children born after in vitro fertilisation

The use of assisted reproductive technologies has increased over the past decades. To date, 8 million children have been born worldwide following assisted reproductive technologies. In Switzerland, this refers to around 2-2.5% of newborn’s every year, this were 2’188 children in 2017. The introduction of this thesis gives an overview of the reasons for increasing global infertility, and of the use of medically assisted reproduction. It also presents the treatment options available today, and the risks associated with them for mothers and offspring. It goes on to describe the methods and data used in the research projects conducted for this thesis. In the following section, the four publications included in this thesis are presented. The first article on children within the Bern IVF Cohort compares the birthweights and birthweight percentiles of children born after natural cycle in vitro fertilisation, to those born after conventional in vitro fertilisation. This shows that the increased risk of small-for-gestational age infants being born may be associated with hyperstimulation of oocyte growth in conventional in vitro fertilisation, especially when high estradiol levels are reached on the day of ovulation induction. The second article uses follow-up data on breastfeeding collected within the Bern IVF Cohort. Breastfeeding prevalence and duration is compared to data from the Swiss Infant Feeding Study, which served as a control population. The findings demonstrate that women after fertility treatment breastfeed their children as much and for as long as mothers in the control population. This suggests that fertility treatment does not affect the potential and ability to breastfeed in Switzerland. The third article relates to the endometrium in natural cycle in vitro fertilisation, where the endometrium is not affected by hormonal stimulation. Data on endometrial thickness was collected from women during their first treatment cycle and the outcome measured, was successful pregnancy. It was shown that both very thin but also thick endometrium is associated with adverse pregnancy outcomes in natural cycle in vitro fertilisation. The fourth article analyses data from a historical cohort of women under treatment due to repeated implantation failure and recurrent pregnancy loss from 2014-2018. The two conditions seem to be associated with chronic endometritis, and their discussion is controversial: so far, no agreement on a standardised diagnosis or treatment has been reached. The aim was to assess the effect of endometrial diagnostic biopsy on subsequent treatment in cases of chronic endometritis, which was introduced in 2016, compared to hysteroscopic assessment alone. This demonstrated that diagnostic endometrial biopsy and subsequent treatment of chronic endometritis shortens time-to-pregnancy and live birth

Gonadotropin Stimulation Reduces the Implantation and Live Birth Rate but Not the Miscarriage Rate of Embryos Transferred When Compared to Unstimulated In Vitro Fertilization.

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

Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study.

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

Investigational medicinal products, related costs and hospital pharmacy services for investigator-initiated trials: A mixed-methods study.

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

COVID-19 Information-Seeking, Health Literacy, and Worry and Anxiety During the Early Stage of the Pandemic in Switzerland: A Cross-Sectional Study.

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

Health-related quality of life before and during the COVID-19 pandemic in Switzerland: a cross-sectional study.

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

Euphrasia Eye Drops in Preterm Neonates With Ocular Discharge: A Randomized Double-Blind Placebo-Controlled Trial

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. Keywords: Euphrasia drops; complementary medicine; congenital nasolacrimal duct obstruction; ocular discharge; preterm neonate

Thin Endometrium Is Also Associated With Lower Clinical Pregnancy Rate in Unstimulated Menstrual Cycles: A Study Based on Natural Cycle IVF

Introduction: Does the endometrial thickness (EMT) at the time of follicle aspiration correlate with the pregnancy rate in unstimulated menstrual cycles?Materials and Methods: This is a retrospective, observational single center study.105 women with regular menstrual cycles undergoing their first NC-IVF cycle with an embryo transfer were analyzed. Clinical pregnancy and live birth rates were calculated and data were adjusted for women's age, cycle day of follicle aspiration and body mass index (BMI).Results: Age of participants was 35.0 y [32.0; 37.0]. Follicle aspiration was performed on day 14.0 [12.0; 15.0] of the cycle. Total clinical pregnancy rate was 24.8% and live birth rate 15.2% per transfer. Pregnancy rate in women with endometrial thickness ≤7 mm (n = 27) was 7.4 and 30.8% in women &gt;7 mm (n = 78) (OR 5.56, 1.22–25.36) (P = 0.03). Live birth rates were not significantly different. Quadratic regression analysis revealed lower pregnancy rates in women with thin (around &lt;8 mm) as well as with thick (around &gt;11 mm) endometria. P-value after crude quadratic analysis was 0.028 and after adjustment for age, day of aspiration and BMI was 0.039. Significance was not reached for live birth rates.Conclusion: Thin endometrium should also be considered as an independent negative prognostic factor for achieving pregnancy in women without ovarian stimulation

The greater incidence of small for gestational age newborns after gonadotropin-stimulated in vitro fertilization with a supra-physiological estradiol level on ovulation trigger day.

INTRODUCTION Reproductive scientists have postulated various risk factors for lower birthweight following conventional gonadotropin stimulated in vitro fertilization compared to 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's 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, as they adjust 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 supra-physiological estradiol levels in maternal serum on ovulation trigger day (unadjusted odds ratio 4.58; 95% confidence interval 1.35 to 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 to 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 to natural-cycle in vitro fertilization. This higher risk is significantly associated with supra-physiological estradiol levels. We propose a reduction in the dosage of gonadotropin to minimize the risk of small for gestational age and future health consequences. This article is protected by copyright. All rights reserved

Evolution of host plant use and diversification in a species complex of parasitic weevils (Coleoptera: Curculionidae)

Weevils (Coleoptera: Curculionoidea) represent one of the most diverse groups of organisms on Earth; interactions with their host plants have been recognized to play a central role in their remarkable diversity, yet the exact mechanisms and factors still remain poorly understood. Using phylogenetic comparative analyses, here we investigate the evolution of host use and its possible role in diversification processes of Rhinusa and Gymnetron, two closely related groups of weevils that feed and develop inside plant tissues of hosts within the families Scrophulariaceae and Plantaginaceae. We found strong evidence for phylogenetic conservatism of host use at the plant family level, most likely due to substantial differences in the chemical composition of hosts, reducing the probability of shifts between host families. In contrast, the use of different plant organs represents a more labile ecological trait and ecological niche expansion that allows a finer partitioning of resources. Rhinusa and Gymnetron weevils initially specialized on plants within Scrophulariaceae and then shifted to the closely related Plantaginaceae; likewise, a gall inducing behavior evolved from non-galler weevils, possibly in response to resource competition, as galls facilitate larval development by providing enhanced nutrition and a favorable microhabitat. Results from trait-dependent diversification analyses suggest that both use of hosts within Plantaginaceae and parasitism on fruits and seed capsules are associated with enhanced diversification of Rhinusa and Gymnetron via low extinction rates. Our study provides quantitative evidence and insights on the ecological factors that can promote diversification in phytophagous insects that feed and develop inside plant tissues