Low dose aspirin in the prevention of recurrent spontaneous preterm labour - the APRIL study: A multicenter randomized placebo controlled trial

Background: Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial. Methods/design: Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22-37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo. Discussion: This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth. Trial registration: Clinical trial registration number of the Dutch Trial Register: NTR 5675. EudraCT-registration number: 2015-003220-31

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study) : A multicentre, randomised, double-blinded, placebo-controlled trial

Funding: MdB, LV, TN, BM, MO and CdG received funding from ZonMw, The Dutch Organisation for Health Research and Development (grant number 836041006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)

Abstract Background Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020

Prevention of neonatal late-onset sepsis associated with the removal of percutaneously inserted central venous catheters in preterm infants

Objectives: Indwelling central venous catheters are the most important risk factors for the development of sepsis attributable to coagulase-negative staphylococci among preterm infants admitted to neonatal intensive care units. In addition, removal of a central venous catheter also may cause coagulase-negative staphylococci sepsis, which may be prevented by the short-term administration of an anti-staphylococcal agent during the procedure of removal. The administration of a specific anti-staphylococcal agent (cefazolin) was evaluated for the prevention of central venous catheter removal-associated coagulase-negative staphylococci sepsis. Design: A prospective, open, randomized, controlled intervention study. Setting: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital. Patients: Eighty-eight preterm infants (gestational age Intervention: From April 2007 to January 2010, infants were randomized to receive two doses of cefazolin during removal of the percutaneously inserted central venous catheter (intervention group, n = 44) or no antimicrobial agent (control group, n = 44). Percutaneously inserted central venous catheter removal-associated sepsis was defined as sepsis occurring Measurements and Main Results: Clinical characteristics and central venous catheter duration did not show differences between both groups. Five infants (11%) of the control group developed coagulase-negative staphylococci sepsis <48 hrs after removal of the percutaneously inserted central venous catheter compared to none (0%) in the intervention group (p = .021). Conclusions: Two doses of the anti-staphylococcal agent cefazolin during the procedure of removal of a percutaneously inserted central venous catheter were effective in the prevention of coagulase-negative staphylococci sepsis. It is recommended to include this regimen in the guidelines on management of central venous catheters in very-low-birth-weight infants. (Pediatr Crit Care Med 2011; 12:445-448

The first fungi: mode of delivery determines early life fungal colonization in the intestine of preterm infants

Aim: The role of intestinal fungi in human health and disease is becoming more evident. The mycobiota composition and diversity of preterm infants is affected by interactions with bacteria and clinical variables. In this study, we aimed to characterize the composition and the diversity of the preterm infant mycobiota and the effect of clinical variables on it in the first six postnatal weeks.Methods: Preterm infants (n = 50) and full-term infants (n = 6) admitted to Isala Women and Children’s hospital (Zwolle, The Netherlands) who were born during 24-36 or 37-40 weeks of gestation, respectively, were included in this study. Feces were collected during the first six postnatal weeks (n = 109) and their mycobiota composition and diversity were characterized by ITS2 amplicon sequencing.Results: Composition analyses identified fungi and other eukaryotic kingdoms, of which Viridiplantae was most abundant. Of the fungal kingdom, Ascomycota and Basidiomycota were the first and second most prominent phyla in early life of all infants. Candida was the most abundant genus in the first six weeks of life and increased with gestational and postnatal age. Fungal phylogenetic diversity remained stable in the first six postnatal weeks. The individuality and the mode of delivery were identified as significant predictors for the variation in the mycobiota composition. Vaginally delivered infants were enriched in Candida spp., whereas infants delivered through emergency C-section were characterized by Malassezia spp.Conclusion: These results indicate that fungi and other eukaryotic kingdoms are detected in the intestine of preterm and full-term infants in the first six postnatal weeks. Similar to the microbiota, colonization of the preterm intestine with fungi is determined by clinical variables including individuality and mode of delivery