Purpose As part of the European risk management plan of a 91-day extended levonorgestrel-containing combined oral contraceptive (COCLNG), a study was performed to assess its safety. This analysis was conducted to examine delayed pregnancy detection and return to fertility with extended combined oral contraceptives (COC). Methods We conducted a retrospective cohort study in new users of 91-day COCLNG or 28-day COCLNG within a US-based healthcare claims database from 2006 to 2017. Delayed pregnancy detection during current COCLNG exposure was defined as the time between estimated pregnancy start and first prenatal care encounter. Additionally, the time between estimated pregnancy start and COCLNG discontinuation was measured. To measure return to fertility, pregnancy rates were estimated among females who discontinued treatment. 91-day COCLNG users were propensity score-matched to 28-day COCLNG users. Hazard ratio for pregnancy was calculated using Cox proportional hazards models. Results The 91-day and 28-day COCLNG users had 25 593 and 76 586 treatment episodes, respectively. The median time to pregnancy detection was 64.5 and 61.0 days (p = 0.24) in users of 91-day COCLNG and 28-day COCLNG. The median exposure time to treatment after estimated pregnancy start was 54.0 and 38.0 days (p < 0.01). In the fertility analysis, pregnancy rates were 54.82 (95% CI, 50.05-59.93) and 69.30 (95% CI, 64.98-73.82) per 1000 person-years in extended COCLNG discontinuers and 28-day COCLNG discontinuers. The adjusted hazard ratio of pregnancy was 0.77 (95% CI, 0.69-0.85). Conclusions Small differences were observed for pregnancy rates and delayed pregnancy detection between 91-day extended COCLNG and 28-day COCLNG, which may be related to the longer days' supply of extended COCLNG. Differences in the fertility analysis may be related to unmeasured residual confounding.

Large global inequalities in assisted reproduction technology (ART) utilisation have existed ever since the introduction of ART. The reasons for these inequalities are multifactorial and include national wealth and affordability, pronatalist policies, regulatory differences in provision, and sociocultural components such as racial, gender and educational inequalities. Examining ART utilisation across the largest world economies (G20 countries) in 2016 (the most recent year with publically available data) reveals significant inequality, which is highly correlated to gross domestic product per capita, a measure of national wealth, and to provision of government funding and/or insurance coverage for in vitro fertilisation and intracytoplasmic sperm injection. A strong negative correlation with the Gender Inequality Index is also noted. The gap in ART utilisation rate will only begin to close once the majority of nations introduce more affordable ART treatment, instigate pronatalist policies, and implement changes in education, attitudes and behaviours to minimise racial and gender inequalities; however, achieving all of these changes may be a very difficult target to attain for many poorer economies, regardless of their size.

Objective As part of the risk management plan in Europe, this study was conducted to characterize drug utilization patterns of Seasonique, a 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG). Methods A retrospective observational study was conducted in France, Italy and Belgium using electronic medical record databases obtained from general practitioners (GPs) in all participating countries and gynecologists in France from 2015 to 2018. The study population included women receiving >= 1 prescription of 91 day COCLNG during the study period. Prescribing patterns of 91 day COCLNG were examined including: (1) treatment duration; (2) indication; (3) use of combined oral contraceptive (COC) before 91 day COCLNG initiation; and (4) switch from and to combined hormonal contraceptives (CHCs) or other contraceptives. Results Totals of 235, 220, 207 and 659 women using 91 day COCLNG were identified in French, Italian and Belgian GP, and French gynecologist databases, respectively. Across databases, 46-76% of women were prescribed a single 91 day COCLNG prescription and median treatment duration ranged from 3 to 6 months. The most common indication was contraception (42-81%), followed by menstrual migraines (2-14%). Use of COC during the 6 months prior to 91 day COCLNG initiation was 14% across GP databases, but was lower (8%) in the French gynecologist database. The frequency of switching from 91 day COCLNG to CHCs or other contraceptives was generally low (5-12%), with the highest proportion being among patients of French gynecologists. Conclusions Findings indicate that 91 day COCLNG was prescribed for relatively short durations and predominantly as indicated for contraception. Most results were comparable across all participating countries.

Are safety and effectiveness of Ovaleap® (follitropin alfa), and Gonal-f®, comparable in one treatment cycle of ART in routine clinical practice? Safety in terms of incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, were similar between Ovaleap® and Gonal-f®. Ovaleap® (Theramex), a r-hFSH, is a biosimilar medicinal product to Gonal-f® (Merck). As a biosimilar, it went through a rigorous series of physio-chemical, in vitro, in vivo tests and confirmatory Phase I and III studies, to demonstrate similarity/equivalence in quality, safety and efficacy to the reference medicinal product, per the European Medicines Agency (EMA) guidelines. Ovaleap® was approved by the EMA in 2013 for use at the same dose and for the same therapeutic indications as Gonal-f®. Further outcome data from a broader patient population on safety and live birth outcomes provides clinically important insights on newly introduced FSH medicines. SOFIA (Safety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies) was a multi-national, comparative, non-interventional, prospective cohort study. The study was performed at 56 centers specializing in ART from six European countries, (Belgium, France, Germany, Italy, Spain, and the United Kingdom) from January 2017 to September 2019 and comprised of 817 infertile women undergoing controlled ovarian hyperstimulation in one treatment cycle for ART The study population comprised of infertile women undergoing controlled ovarian hyperstimulation for ART, who were administered Ovaleap® or Gonal-f® and were naïve to any FSH containing products. Eligible patients were enrolled at a ratio of approximately 1:1, both within and between countries. They were followed up to 30 days after the last FSH dose administration. Women who had a confirmed clinical pregnancy were followed until the end of the pregnancy or until delivery. A total of 408 and 409 women who were administered Ovaleap® or Gonal-f®, respectively, were eligible for analysis. A total of 382 patients (94%) in the Ovaleap® and 390 patients (95%) in the Gonal-f® cohort completed FSH treatment (up to oocyte maturation triggering), respectively. The two cohorts were generally similar with regard to demographic and baseline characteristics. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p > 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% Grade II, and 0.5% versus 0.2% Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively) and without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31%, live birth rates 27% and 26% in the Ovaleap® and Gonal-f® cohorts, respectively. Since treatment was non-randomised, the study may have been susceptible to selection bias. This was addressed at both the design stage, by balancing recruitment to a 1:1 ratio for Ovaleap® and Gonal-f® treatments, and also at the analysis stage in which, a univariate analysis was performed. Wider implications of the findings: Findings from this first large European prospective comparative real-world SOFIA study demonstrated that effectiveness (pregnancy and delivery rates) and safety (risk and severity of OHSS), were similar between Ovaleap®and Gonal-f® treatments. Ovaleap, a biosimilar r-hFSH is therefore a suitable option for follicular stimulation in routine clinical practice. EUPAS17328

Background Ovaleap® (follitropin alfa), a recombinant human follicle stimulating hormone, is a biosimilar medicinal product to Gonal-f® and is used for ovarian stimulation. The main objective of this study was to assess the safety and effectiveness of Ovaleap® compared to Gonal-f® in one treatment cycle in routine clinical practice. Methods Safety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies (SOFIA) was a prospective cohort study conducted in six European countries. Eligible patients were infertile women undergoing superovulation for assisted reproductive technology, who were administered Ovaleap® or Gonal-f® for ovarian stimulation and were naïve to follicle stimulating hormone treatment. The recruitment ratio was 1:1. The primary endpoint was incidence proportion of ovarian hyperstimulation syndrome (OHSS) and the secondary endpoint was OHSS severity (Grades I, II, III). The effect of risk factors or potential confounders on the odds ratio for OHSS incidence as well as treatment effect on OHSS incidence was explored using univariate logistic regression. Pregnancy and live birth rates were also assessed. Results A total of 408 women who were administered Ovaleap® and 409 women who were administered Gonal-f® were eligible for analysis. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® cohort and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p > 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% for Grade II, and 0.5% versus 0.2% for Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively), without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31% and live birth rates were 27% and 26%, in the two cohorts, respectively. Conclusions Findings from the SOFIA study indicate that the incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, are similar between Ovaleap® and Gonal-f® treatments and corroborate the safety and effectiveness of Ovaleap® as a biosimilar to Gonal-f®.

Abstract Study question Are there any correlations between a country’s wealth determined by GDP per capita and its total fertility rate (TFR) and utilisation of ART in Europe? Summary answer There is strong correlation across Europe between GDP and utilisation of ART. This correlation does not exist when only investigating the European Economic Area (EEA) What is known already The number of documented ART cycles has increased significantly from 203,893 cycles in 1997 (first European report) to 918,159 in 2016. During the same period, growth was observed in European GDP and, to a lesser extent, TFR following a significant and prolonged decline. Global data suggest that utilisation rate is higher in developed countries, speculated to be due to either generous reimbursement systems or higher affordability for patients paying out of pocket. This study analysed for the first time the relationships between national GDP, TFR and utilisation in Europe both as a whole, and specifically the more affluent EEA Study design, size, duration This study was an analysis of publicly available primary international reports: total cycles in the European IVF-monitoring Consortium (EIM) and TFR, GDP and population size from the World Bank indicators (https://data.worldbank.org/indicator). The period studied ranged from the first EIM report for 1997 (published in 1999) to the 20th report for 2016 (published in 2020). Participants/materials, setting, methods TFR was described as births per women (BPW) and country wealth was presented as GDP per capita in US Dollars. Utilisation rate was defined as the total national number of cycles (fresh IVF and ICSI, and frozen embryo transfer) divided per population, and presented as cycles per million (CPM). When utilisation was not reported, total cycles were projected by proportional calculation. Pearson Correlations were calculated using Sigmaplot for utilisation, GDP and TFR in 2016 Main results and the role of chance Forty countries were included in the EIM report for 2016, of which 18 reported in full. The median utilisation rate was 1280 CPM (range 162 - 3,156) and median TFR was 1.6 BPW (range 1.26 - 2.73); only one country, Kazakhstan, had a TFR above the natural fertility replacement level of 2.1 BPW. Mean GDP was $31604 per capita (range $10,610 - $110,650). There was no correlation between TFR and utilisation or between TFR and GDP, however there was a significant positive correlation between GDP and CPM (correlation coefficient = 0.428; P = 0.00661). Compared to Europe as a whole, analysis of only the EEA countries – EU member states plus Norway, Iceland, and Switzerland – revealed a similar median TFR (1.59), but a 27% increase in the utilisation rate to 1629 CPM (range: 317 – 3157) and 24% rise in GDP per capita to $39,300 (range: $19,885- $110,650). For the EEA, no significant correlations were observed, including between GDP and utilisation (correlation coefficient = 0.131; P = 0.507). Additionally, there was no significant correlation between TFR and GDP in the EU for the period of 1997 – 2016. Limitations, reasons for caution The data is a snapshot of a single year, but we observed similar outcomes in previous years. Projection calculation of utilisation in partially reporting countries may cause bias, however, with a reporting level of 92% (1347 of 1467 clinics), this bias is probably very limited. Wider implications of the findings: Findings of this study confirm that there are strong disparities in the availability of ART even in Europe. This difference does not exist in the more affluent countries in Europe suggesting that the reason for lower utilisation in lower-income countries being reduced affordability. Trial registration number NA

AIM:To explore the relationships between total fertility rate (TFR), utilization of assisted reproduction technology (ART), and gross domestic product (GDP) per capita in Europe. MATERIALS AND METHODS:Analysis of total ART cycles obtained from the latest European IVF-Monitoring Consortium (EIM) report for 2016. TFR, GDP and population size for that year were found in relevant World Bank data documents. In addition, this study compared two subgroups in Europe: developed economies and economies in transition, as defined by the UN. Pearson Correlations were calculated using Sigmaplot for utilization, GDP and TFR. RESULTS:Forty countries were included in the 2016 EIM report. The mean utilization rate was 1,391 cycles per million population (C/M) (range = 162-3156) and mean TFR was 1.61 (range = 1.26-2.73). Mean GDP was $35,072 per capita (range = $10,610-$110,650). There was no correlation between TFR and utilization or GDP, however there was a significant positive correlation between GDP and utilization (correlation coefficient = 0.428; p = 0.00661). In the developed economies (n = 28) GDP and utilization were roughly 3-times higher than in the economies in transition (n = 11) ($42,710 vs $15,630; 1,674 vs 671), with a slightly lower TFR (1.58 vs 1.67). In the developed economies there was no correlation between GDP, TFR, and utilization, while in the economies in transition, the only significant correlation was GDP vs TFR (r = 0.69; p = 0.017). CONCLUSIONS:There is a strong correlation across Europe between GDP and utilization of ART. This correlation does not exist within the developed economies. In Europe the utilization of ART treatment is dependent on national wealth and not on the TFR in the country.

OBJECTIVES:To compare the safety profile of Seasonique, a 91-day levonorgestrel-containing combined oral contraceptive (COCLNG), to 28-day COCLNG regarding the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). STUDY DESIGN:A new user cohort study was conducted in a US health care database from 2006 to 2017. Each 91-day COCLNG treatment episode in females was matched to up to four 28-day COCLNG treatment episodes by propensity score. We identified VTE cases in either (1) an inpatient setting with ICD-9 and ICD-10 diagnosis codes of PE and/or DVT in the primary position, or (2) an outpatient setting with ICD-9 or ICD-10 diagnosis codes of DVT in conjunction with an anticoagulant medication dispensing or alteplase (thrombolytic) during the 30-day period following the date of DVT diagnosis. VTE was validated using medical records. We assessed the study endpoints in the two cohorts using incidence rates and Cox proportional hazards models adjusted for potential confounders. RESULTS:Of the 25,593 treatment episodes in 91-day COCLNG and 76,586 treatment episodes in 28-day COCLNG, 35 and 68 patients had VTEs, respectively, corresponding to a hazard ratio (HR) of 1.40 (95% confidence interval [CI], 0.90-2.19). The VTE algorithm had a positive predictive value of 76.4% (95% CI, 66.2%-84.8%). ATEs were recorded in 13 and 28 episodes, respectively, with a corresponding HR of 1.21 (95% CI, 0.58-2.53). CONCLUSIONS:These results do not indicate a significant difference between 91-day COCLNG and 28-day COCLNG in terms of VTE or ATE risk. IMPLICATIONS:Compared to use of 28-day COCLNG, use of 91-day extended COCLNG was not associated with a significant difference in risk of venous and arterial thromboembolism.

View responses to this article:Reply: RE: a cost-effectiveness modeling evaluation comparing a biosimilar follitropin alfa preparation with its reference product for live birth outcome in Germany, Italy, and Spain

Background: IVF is now a wide spread procedure globally, and currently 65 countries report annually all or part of their IVF/ICSI cycles, from which the International Committee Monitoring progress in Assisted Reproduction Technology (ICMART) published its report. There is considerable variation in the utilization (number of cycles per population) globally. Aims: The objectives of this study were to assess whether utilization is related to national wealth, presented as gross domestic product (GDP), and whether the GDP has any effect on success in IVF treatment, mainly delivery and clinical pregnancy rates. Results: The results demonstrated a significant positive correlation between utilization and GDP (CC = 0.563, p = 0.00000194), and both utilization and GDP have strong negative correlations to successful outcome of the treatment-clinical pregnancy rate (CC: -0.460, p = 0.00015; CC: -0.399, p = 0.0012, respectively) and delivery rates (cc = -0.396, p = 0.00484; cc = -0.3, p = 0.0179, respectively). Conclusions: Poor nations have less utilization of IVF, probably due to the limited affordability of the treatment, but reassuringly do not seem to have less success in the treatment. Further research is required to fully understand the implications of these correlations and to better design national and international fertility policies.

This article discusses the role of hormone replacement therapy (HRT) in the management of menopausal symptoms, and specifically considers the advantages of different types and preparations of HRT, based on the current medical evidence. The menopause is a normal life event for women, not an illness or a medical condition. However, the effects of the menopause often have a negative impact on women’s wellbeing and quality of life. Furthermore, the low oestrogen levels and other biological changes that occur in these women are also associated with an increased risk of cardiovascular disease, osteoporosis, diabetes, and dementia. In addition to hot flushes and sweats, symptoms include mood changes, memory loss, urogenital atrophy, reduced libido, sleep disturbances, joint pains, and muscle stiffness.1 These symptoms can be non-existent, or can last for a few years or even decades. Much of the negative publicity surrounding HRT stems from misinterpretation by the media of the findings from the Women’s Health Initiative (WHI) study,2 published more than a decade ago. Many women and healthcare professionals are still unnecessarily concerned about the perceived risks of HRT, resulting in a significant proportion of women currently being refused HRT and often being inappropriately offered antidepressants. There is clear evidence to support that, …

Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids, derived mostly from fish oil, that have a significant anti-inflammatory effect. Data from animal studies support their role in the reproductive mechanism, and recent human studies suggest a positive effect on sperm quality and natural conception. Their general role in human fertility, and specifically in IVF treatment, however, is not clear. A few small, prospective cohort studies have examined the relationship between serum PUFAs and outcome measures and success in IVF, with conflicting results. Some have demonstrated a better chance of live birth with increased levels of serum omega-3 PUFAs, whereas others have failed to show such a correlation, and the reasons for such differences are not clear. Moreover, no well-designed, published studies have assessing whether the administration of omega-3 PUFAs before IVF treatment can improve clinical pregnancy and live birth rates. The development of safe and well-tolerated pharmaceutical forms of the active omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), mean that assessment of this question is now possible and future studies are warranted.

BACKGROUND:Despite its high prevalence, opioid-induced constipation (OIC) remains under-recognised and undertreated, and its true impact on wellbeing and quality of life (QoL) may be underestimated.METHODS:A quantitative, questionnaire-based international survey was conducted.RESULTS:Weak-opioid users appeared as bothered by constipation as strong-opioid users (38% vs 40%, respectively; p = 0.40), despite it causing less-severe physical symptoms and impact on QoL. Strong-opioid users meeting Rome IV OIC criteria appeared to experience greater symptomatic and biopsychosocial burden from constipation than those not satisfying these criteria. Almost one-fifth of respondents were dissatisfied with their current constipation treatment and around one-third found balancing the need for adequate pain relief with constipation side effects challenging. Consequently, more than half failed to adhere to their prescribed treatment regimens, or resorted to suboptimal strategies, e.g. 40% reduced their opioid intake, to relieve constipation. Almost 60% of healthcare professionals did not adequately counsel patients about constipation as a common side effect of opioid use.CONCLUSIONS:Findings suggest that both weak- and strong-opioid users suffer comparable bother and decreased QoL, Rome IV criteria can identify patients with more-severe OIC, but may underdiagnose patients showing fewer symptoms, and increased education is needed to manage patients' expectations and enable improved OIC self-management.

Sir, I read with great interest the detailed study of Lind et al. (2017), in which they found reduced live-birth rates after IVF/ICSI in women with previous unilateral oophorectomy. These are important results with far reaching implications to patients, however, they are in sharp contrast to findings in the majority of studies we (Lass et al., 1997) and others published over the last 30 years, summarised by Khan et al. (2014). There has been wide consensus that women with a single ovary have a poorer response to stimulation, require more gonadotrophins, and yield fewer oocytes and embryos. However, by mechanisms which are not fully understood, the clinical pregnancy rate and much less reported live pregnancy rate were not reduced and are similar to the reference group (Lass, 1999; Khan et al., 2014). The weakness of all these studies, including the current one of Lind et al., is that all were retrospective historic observational studies with their inherent biases. None of them were prospective randomised control studies. I believe that such prospective study is long overdue. I suggest also performing a systematic literature review and meta-analysis of the dozen or so published observational studies to try to understand the real clinical effect of unilateral oophorectomy on life birth rate in IVF/ICSI. References

Vaginal progesterone via capsule, gel or tablet is the most common route for luteal phase support (LPS) in Europe. Although there is a wealth of data comparing products used at other stages of assisted reproductive technology cycles, there is a lack of systematically identified evidence comparing the wide range of vaginal progesterone products. This systematic review queried the MEDLINE, Embase and Cochrane Library databases on 30 June 2016 to identify head-to-head randomized controlled trials (RCTs) comparing the efficacy or safety of vaginal progesterone preparations (Crinone, Cyclogest, Lutigest or Utrogestan Vaginal) for LPS in assisted reproductive technology cycles. Of 1914 results, 18 RCTs were included. No significant difference in clinical pregnancy rate was identified in comparisons of Utrogestan Vaginal with Crinone. Utrogestan Vaginal and Lutigest were non-inferior to Crinone in ongoing pregnancy rate comparisons. Differences in patient-reported perineal irritation with Crinone and Lutigest were not significantly different to Cyclogest. In studies comparing varying timing or dosage of Utrogestan Vaginal or Crinone, no significant differences were observed. These results suggest Crinone, Cyclogest, Lutigest and Utrogestan Vaginal represent equally safe and effective choices of vaginal progesterone for LPS in assisted reproductive technology cycles. Future quantitative analyses could provide further support for these findings.

This prospective observational post-marketing survey aimed at studying the efficacy and convenience of the follitropin alpha filled-by-mass (FbM) pre-filled pen for patients in routine use. These data were analysed among 3196 non-selected treatment cycles and couples in seven Northern European countries. Valuable information was also obtained regarding the routine assisted reproduction treatment protocols used in Northern Europe. Out of 3196 cycles, human chorionic gonadotrophin (HCG) was administered in 3104 (97.2%), and an embryo transfer was carried out in 2766 cycles (86.5%). A positive HCG was recorded in 997 cycles (31.2% per started cycle and 36.0% per embryo transfer). The overall clinical pregnancy rate was 23.1% (738/3196) and per embryo transfer it was 26.7% (738/2766), with a miscarriage rate of 3.4% (95/2766) per embryo transfer or 9.5% (95/997) per positive HCG. Among the 732 elective single embryo transfers (eSET), the rate of positive HCG was 38.0% and the clinical pregnancy rate was 29.6%, suggesting that eSET is a valuable option in routine assisted reproduction. Although minor differences were observed between countries, the follitropin alpha FbM pre-filled pen proved clinically effective, was generally well tolerated, and both the women and nurses/midwives found the training easy.