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An international collaborative meta-analysis on mortality in all ongoing or completed randomized clinical trials evaluating hydroxychloroquine or chloroquine for COVID-19

IntroductionVaginal progesterone and a cervical pessary are both interventions that are investigated for the prevention of preterm birth (PTB). Thus far, beneficial or harmful effects of these interventions on long-term child health and development are described, but evidence is not robust enough to draw firm conclusions. With this follow-up study, we intent to investigate if progesterone or a pessary is superior for the prevention of PTB considering the child’s health at 4–6 years of corrected age.Methods and analysisThis study is a follow-up study of the Quadruple-P trial; a multicentre, randomised clinical trial (NL42926.018.13, Eudractnumber 2013-002884-24) which randomises women with an asymptomatic midtrimester short cervix to daily progesterone or a pessary for the prevention of PTB. All children born to mothers who participated in the Quadruple-P study (n=628 singletons and n=332 multiples) will be eligible for follow-up at 4–6 years of corrected age. Children will be assessed using parental questionnaires. Main outcomes are child (neuro)development and behaviour. Other outcomes include child mortality, growth and general health. A composite of adverse child outcomes will be compared between the progesterone and pessary groups reporting OR and the corresponding 95% CI. Analyses will be performed separately for singletons and multiples and using the intention-to-treat approach.Ethics and disseminationThe Medical Research Ethics Committee from Amsterdam UMC confirmed that de Medical Research Involving Human Subjects Act (WMO) did not apply to our study (W20_481 #20.531). Results will be published in a peer-reviewed journal and shared with stakeholders and participants. This protocol is published before analysis of the results.Trial registration numberDutch Trial Register (NL9646).

IntroductionThe use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age.Methods and analysisThis is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design.Ethics and disseminationInstitutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences.Trial registration numberThe APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Introduction The ProTWIN trial previously showed no beneficial effect of treatment with a cervical pessary vs usual care to prevent preterm birth in women with a multiple pregnancy. However, in women with a midtrimester short cervix (

Introduction The ProTWIN trial previously showed no beneficial effect of treatment with a cervical pessary vs usual care to prevent preterm birth in women with a multiple pregnancy. However, in women with a midtrimester short cervix (

OBJECTIVE: We recently found in a randomized clinical trial (ProTWIN) that cervical pessary prevented preterm birth and improved neonatal outcome in women with a multiple pregnancy and a cervical length (CL)

Objective A recent randomized clinical trial (ProTWIN) showed that a cervical pessary prevented preterm birth and improved neonatal outcome in women with multiple pregnancy and cervical length (CL)

OBJECTIVE: The ProTWIN Trial (NTR1858) showed that in women with a multiple pregnancy and a cervical length less than the 25(th) percentile (38mm), prophylactic use of a cervical pessary reduced the risk of adverse perinatal outcome. We investigated whether other maternal or pregnancy characteristics collected at baseline can improve identification of women with the most probable benefit from pessary placement. METHODS: ProTWIN is a multicenter randomized trial in which 808 women with a multiple pregnancy were assigned to pessary or control. Using this data we developed a multivariable logistic model comprising treatment, cervical length, chorionicity, pregnancy history and number of fetuses and the interaction of these variables with treatment as predictors of adverse perinatal outcome. RESULTS: Short cervix, monochorionicity and nulliparity were predictive factors for a benefit from pessary insertion. History of previous preterm birth and triplet pregnancy were predictive factors of possible harm from pessary. The model identified 35% of women as benefiting (95% CI: 32% to 39%), which is 10% more than using cervical length only (25%) for pessary decisions. The model had acceptable calibration. We estimated that using the model to guide the choice of pessary would reduce the risk of adverse perinatal outcomes significantly from 13.5% when no pessary is inserted to 8.1% (absolute risk reduction 5.4%, 95% CI: 2.1% to 8.6%). CONCLUSIONS: We developed and internally validated a multivariable treatment selection rule, with cervical length, chorionicity, pregnancy history and number of fetuses. If externally validated, it can be used to identify women with a twin pregnancy who benefit from a pessary, and therefore a reduction in adverse perinatal outcomes in twin pregnancies can be anticipated.

In most pregnancies the synergy between mother and her unborn child is adequately balanced, resulting in the birth of the baby at the end of an uncomplicated pregnancy. Unfortunately, not all pregnancies and deliveries remain in such optimal balance. Many new and existing interventions can be offered to pregnant women who face a problem in pregnancy or during labour. In order to guide clinical as well as policy decision making, evaluation research is needed to establish evidence on effectiveness and potential harm of these interventions. A randomized controlled trial (RCT) is worldwide considered as the best instrument to evaluate the effectiveness of medical interventions. Systematic reviews and meta-analyses subsequently aggregate the evidence to give a more balanced answer to a research question. In summary we face the following problems in evaluation research in obstetric interventions: 1) a lack of standardization in the selection and operationalization of outcomes. This may lead to inefficiency in research and waste of resources. 2) a lack of systematic follow-up data of randomized controlled trials, leaving a blind spot in clinical research. 3) a gap between clinical research and its impact in clinical decisions. Patients therefore do not fully benefit from the available evidence. This thesis focuses on improving evaluation research on obstetric interventions. The aims are to: • develop a core outcome set that can be used in obstetrical evaluation studies • measure long-term outcomes of obstetrical evaluation studies • integrate outcomes of obstetrical evaluation studies in order to guide clinical decision making.