A User-Driven Framework for Dose Selection in Pregnancy:Proof of Concept for Sertraline

Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user-driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best-evidence antenatal dose for sertraline. After initial development and evaluation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was reviewed and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a case study, was formulated using this approach and endorsed for clinical use by the working committee. Future applications of the framework for other drugs can further demonstrate its suitability for developing best evidence, acceptable and clinically feasible antenatal doses

Perceived barriers and facilitators for model-informed dosing in pregnancy:a qualitative study across healthcare practitioners and pregnant women

Background: Most women use medication during pregnancy. Pregnancy-induced changes in physiology may require antenatal dose alterations. Yet, evidence-based doses in pregnancy are missing. Given historically limited data, pharmacokinetic models may inform pregnancy-adjusted doses. However, implementing model-informed doses in clinical practice requires support from relevant stakeholders. Purpose:To explore the perceived barriers and facilitators for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women. Methods: Online focus groups and interviews were held among healthcare practitioners (HCPs) and pregnant women from eight countries across Europe, Africa and Asia. Purposive sampling was used to identify pregnant women plus HCPs across various specialties prescribing or providing advice on medication to pregnant women. Perceived barriers and facilitators for implementing model-informed doses in pregnancy were identified and categorised using a hybrid thematic analysis. Results: Fifty HCPs and 11 pregnant women participated in 12 focus groups and 16 interviews between January 2022 and March 2023. HCPs worked in the Netherlands (n = 32), the UK (n = 7), South Africa (n = 5), Uganda (n = 4), Kenya, Cameroon, India and Vietnam (n = 1 each). All pregnant women resided in the Netherlands. Barriers and facilitators identified by HCPs spanned 14 categories across four domains whereas pregnant women described barriers and facilitators spanning nine categories within the same domains. Most participants found current antenatal dosing information inadequate and regarded model-informed doses in pregnancy as a valuable and for some, much-needed addition to antenatal care. Although willingness-to-follow model-informed antenatal doses was high across both groups, several barriers for implementation were identified. HCPs underlined the need for transparent model validation and endorsement of the methodology by recognised institutions. Foetal safety was deemed a critical knowledge gap by both groups. HCPs’ information needs and preferred features for model-informed doses in pregnancy varied. Several pregnant women expressed a desire to access information and partake in decisions on antenatal dosing. Conclusions: Given the perceived limitations of current pharmacotherapy for pregnant women and foetuses, model-informed dosing in pregnancy was seen as a promising means to enhance antenatal care by pregnant women and healthcare practitioners.</p

Study protocol: Cost effectiveness of two strategies to implement the NVOG guidelines on hypertension in pregnancy: An innovative strategy including a computerised decision support system compared to a common strategy of professional audit and feedback, a randomized controlled trial

Background: Hypertensive disease in pregnancy remains the leading cause of maternal mortality in the Netherlands. Seventeen percent of the clinical pregnancies are complicated by hypertension and 2% by preeclampsia. The Dutch Society of Obstetrics and Gynaecology (NVOG) has developed evidence-based guidelines on the management of hypertension in pregnancy and chronic hypertension. Previous studies showed a low adherence rate to other NVOG guidelines and a large variation in usual care in the different hospitals. An explanation is that the NVOG has no general strategy of practical implementation and evaluation of its guidelines. The development of an effective and cost effective implementation strategy to improve adherence to the guidelines on hypertension in pregnancy is needed.Methods/Design: The objective of this study is to assess the cost effectiveness of an innovative implementation strategy of the NVOG guidelines on hypertension including a computerised decision support system (BOS) compared to a common strategy of professional audit and feedback. A cluster randomised controlled trial with an economic evaluation alongside will be performed. Both pregnant women who develop severe hypertension or pre-eclampsia and professionals involved in the care for these women will participate. The main outcome measures are a combined rate of major maternal complications and process indicators extracted from the guidelines. A total of 472 patients will be included in both groups. For analysis, descriptive as well as regression techniques will be used. A cost effectiveness and cost utility analysis will be performed according to the intention-to-treat principle and from a societal perspective. Cost effectiveness ratios will be calculated using bootstrapping techniques

Nationwide implementation of a decision aid on vaginal birth after cesarean:a before and after cohort study

Woman with a history of a previous cesarean section (CS) can choose between an elective repeat CS (ERCS) and a trial of labor (TOL), which can end in a vaginal birth after cesarean (VBAC) or an unplanned CS. Guidelines describe women's rights to make an informed decision between an ERCS or a TOL. However, the rates of TOL and vaginal birth after CS varies greatly between and within countries. The objective of this study is to asses nation-wide implementation of counselling with a decision aid (DA) including a prediction model, on intended delivery compared to care as usual. We hypothesize that this may result in a reduction in practice variation without an increase in cesarean rates or complications. In a multicenter controlled before and after cohort study we evaluate the effect of nation-wide implementation of a DA. Practice variation was defined as the standard deviation (SD) of TOL percentages. A total of 27 hospitals and 1,364 women were included. A significant decrease was found in practice variation (SD TOL rates: 0.17 control group vs. 0.10 intervention group following decision aid implementation, p=0.011). There was no significant difference in the ERCS rate or overall CS rates. A 21% reduction in the combined maternal and perinatal adverse outcomes was seen. Nationwide implementation of the DA showed a significant reduction in practice variation without an increase in the rate of cesarean section or complications, suggesting an improvement in equality of care

Effectiveness of a cervical pessary for women who did not deliver 48 h after threatened preterm labor (Assessment of perinatal outcome after specific treatment in early labor: Apostel VI trial)

Background: Preterm birth is a major cause of neonatal mortality and morbidity. As preventive strategies are largely ineffective, threatened preterm labor is a frequent problem that affects approximately 10 % of pregnancies. In recent years, risk assessment in these women has incorporated cervical length measurement and fetal fibronectin testing, and this has improved the capacity to identify women at increased risk for delivery within 14 days. Despite these improvements, risk for preterm birth continues to be increased in women who did not deliver after an episode of threatened preterm labor, as indicated by a preterm birth rate between 30 to 60 % in this group of women. Currently no effective treatment is available. Studies on maintenance tocolysis and progesterone have shown ambiguous results. The pessary has not been evaluated in women with threatened preterm labor, however studies in asymptomatic women with a short cervix show reduced rates of preterm birth rates as well as perinatal complications. The APOSTEL VI trial aims to assess the effectiveness of a cervical pessary in women who did not deliver within 48 h after an episode of threatened preterm labor. Methods/Design: This is a nationwide multicenter open-label randomized clinical trial. Women with a singleton or twin gestation with intact membranes, who were admitted for threatened preterm labor, at a gestational age between 24 and 34 weeks, a cervical length between 15 and 30 mm and a positive fibronectin test or a cervical length below 15 mm, who did not deliver after 48 h will be eligible for inclusion. Women will be allocated to a pessary or no intervention (usual care). Primary outcome is preterm delivery <37 weeks. Secondary outcomes are amongst others a composite of perinatal morbidity and mortality. Sample size is based on an expected 50 % reduction of preterm birth before 37 weeks (two-sided test, a 0.05 and beta 0.2). Two hundred women with a singleton pregnancy need to be randomized. Analysis will be done by intention to treat. Discussion: The APOSTEL VI trial will provide evidence whether a pessary is effective in preventing preterm birth in women who did not deliver 48 h after admission for threatened pretermlabor and who remain at high risk for preterm birth

Haemorrhagia post partum; an implementation study on the evidence-based guideline of the Dutch Society of Obstetrics and Gynaecology (NVOG) and the MOET (Managing Obstetric Emergencies and Trauma-course) instructions; the Fluxim study

Contains fulltext : 88435.pdf (publisher's version ) (Open Access)BACKGROUND: One of the most important causes of maternal mortality and severe morbidity worldwide is post partum haemorrhage (PPH). Factors as substandard care are frequently reported in the international literature and there are similar reports in the Netherlands. The incidence of PPH in the Dutch population is 5% containing 10.000 women a year. The introduction of an evidence-based guideline on PPH by the Dutch society of Obstetrics and Gynaecology (NVOG) and the initiation of the MOET course (Managing Obstetrics Emergencies and Trauma) did not lead to a reduction of PPH. This implies the possibility of an incomplete implementation of both the NVOG guideline and MOET-instructions. Therefore, the aim of this study is to develop and test a tailored strategy to implement both the NVOG guideline and MOET-instructions METHODS/DESIGN: One step in the development procedure is to evaluate the implementation of the guideline and MOET-instructions in the current care. Therefore measurement of the actual care will be performed in a representative sample of 20 hospitals. This will be done by prospective observation of the third stage of labour of 320 women with a high risk of PPH using quality indicators extracted from the NVOG guideline and MOET instructions. In the next step barriers and facilitators for guideline adherence will be analyzed by performance of semi structured interviews with 30 professionals and 10 patients, followed by a questionnaire study among all Dutch gynaecologists and midwives to quantify the barriers mentioned. Based on the outcomes, a tailored strategy to implement the NVOG guideline and MOET-instructions will be developed and tested in a feasibility study in 4 hospitals, including effect-, process- and cost evaluation. DISCUSSION: This study will provide insight into current Dutch practice, in particular to what extent the PPH guidelines of the NVOG and the MOET-instructions have been implemented in the actual care, and into the barriers and facilitators regarding guideline adherence. The knowledge of the feasibility study regarding the effects and costs of the tailored strategy and the experiences of the users can be used in countries with a relatively high incidence of PPH. TRIAL REGISTRATION: ClinicTrials.gov NCT00928863

Temporizing management vs immediate delivery in early-onset severe preeclampsia between 28 and 34 weeks of gestation (TOTEM study) : An open-label randomized controlled trial

Peer reviewedPublisher PD

Early nasogastric tube feeding in optimising treatment for hyperemesis gravidarum: The MOTHER randomised controlled trial (Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding)

Background: Hyperemesis gravidarum (HG), or intractable vomiting during pregnancy, is the single most frequent cause of hospital admission in early pregnancy. HG has a major impact on maternal quality of life and has repeatedly been associated with poor pregnancy outcome such as low birth weight. Currently, women with HG are admitted to hospital for intravenous fluid replacement, without receiving specific nutritional attention. Nasogastric tube feeding is sometimes used as last resort treatment. At present no randomised trials on dietary or rehydration interventions have been performed. Small observational studies indicate that enteral tube feeding may have the ability to effectively treat dehydration and malnutrition and alleviate nausea and vomiting symptoms. We aim to evaluate the effectiveness of early enteral tube feeding in addition to standard care on nausea and vomiting symptoms and pregnancy outcomes in HG patients. Methods/Design: The MOTHER trial is a multicentre open label randomised controlled trial ( www.studies-obsgyn.nl/mother ). Women ≥ 18 years hospitalised for HG between 5 + 0 and 19 + 6 weeks gestation are eligible for participation. After informed consent participants are randomly allocated to standard care with intravenous rehydration or early enteral tube feeding in addition to standard care. All women keep a weekly diary to record symptoms and dietary intake until 20 weeks gestation. The primary outcome will be neonatal birth weight. Secondary outcomes will be the 24-h Pregnancy Unique Quantification of Emesis and nausea score (PUQE-24), maternal weight gain, dietary intake, duration of hospital stay, number of readmissions, quality of life and side-effects. Also gestational age at birth, placental weight, umbilical cord plasma lipid concentration and neonatal morbidity will be evaluated. Analysis will be according to the intention to treat principle. Discussion: With this trial we aim to clarify whether early enteral tube feeding is more effective in treating HG than intravenous rehydration alone and improves pregnancy outcome. Trial registration: Trial registration number: NTR4197. Date of registration: October 2nd 2013

Основные положения формирования нового единого сельскохозяйственного налога

Обосновывается введение единого сельскохозяйственного налога как постоянной ставки от стоимости валового дохода предприятий.Обгрунтовується введене єдиного сільськогосподарського податку як постійної ставки до вартості валового доходу підприємств.Introduction of the united agricultural tax is grounded as a permanent size to the cost of gross profit of enterprises

Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial)

Background: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre wit