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

Is breastfeeding useful in the management of neonatal abstinence syndrome?

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Neurofibromatosis type 1 vasculopathy: when to screen?

INTRODUCTION: Case Description. A male infant born after an uneventful pregnancy and delivery was admitted to the neonatology ward on the first day of life because of feeding difficulties. Parenteral nutrition was initiated and continued for two days. Abdominal ultrasound screening showed a vascular malformation in the liver, which was further investigated by magnetic resonance imaging, describing the lesion as an arteriovenous malformation. No other abdominal vascular lesions were found. Favorable progression of drinking behaviour allowed the child to be discharged home on day 8. The appearance of multiple brownish maculae on the back and trunk of the infant by the age of 3 months initiated diagnostic evaluation for neurofibromatosis 1 (NF1). Dermatologic evalution classified the lesions as typical café-au-lait maculae. No axillary or inguinal freckling was found. Ophthalmologic examination showed no abnormalities. Gene analysis revealed a mutation in the NF1 gene; which confirmed the clinical diagnosis of NF1. CONCLUSION Discussion. NF1 is an autosomal dominant disorder with a prevalence of one in 3000 individuals. NF1 diagnosis in patients with negative familial history can have significant delay due to the initial absence of at least two of the seven diagnostic criteria, as defined by the National Institutes of Health consensus statement. Significant vascular lesions are a rare but well-known feature of the disease and routine vascular screening is not recommended. NF1 vasculopathy includes a wide spectrum of vascular abnormalities. The most common lesions are aneurysms or stenoses of the aortic, renal and mesenteric arteries. Arteriovenous malformations are also part of the spectrum. Once a vascular abnormality has been identified screening for other lesions by non-invasive imaging of head, chest and abdomen is justified. Patients with NF1 vasculopathy have a reduced life expectancy when compared with NF1 patients without vasculopathy, especially when arteries of the heart or brain are involved

Genomic variation-guided management in chronic hepatitis C

In 2009, several different research groups simultaneously identified the polymorphisms close to IL28B gene as an important predictor of therapeutic response for chronic hepatitis C (CHC) patients receiving interferon-based treatment using approaches of genome-wide association studies. They also found that these genetic variations were strongly associated with the spontaneous viral clearance of hepatitis C virus (HCV) infection. Following these studies, ITPA gene variants were reported to affect ribavirin-induced anemia and therapeutic outcomes of CHC patients. All these lines of evidence usher in a new genomic era for the management of HCV infection. In this article, advances in recent genome-wide association studies regarding HCV infection, and their impacts on the management of CHC patients will be reviewed. In addition, the clinical usefulness of genomic variations on the addition of direct antiviral agents to current standard of care will be discussed

Ping­pong skull fracture in the newborn: to treat or not to treat ?

Case Description: A 2.870g female infant was born at 38 weeks via vaginal delivery in occipito-posterior position. Because of a prolonged second stage of labour and recurrent late decelerations indicating foetal distress, the delivery was vacuum-assisted with a cup placed on the right side of the forehead. At birth, a depression of the left parietal skull was noted, measuring approximately 5 mm in depth and 40 mm in diameter. The depression had a bony base and no accompanying oedema or hematoma. Neurologic and physical examination revealed no other abnormalities. A thorough review of the perinatal history could not identify a causal trauma. Radiography of the maternal pelvis showed no abnormalities. An X-ray of the skull was performed to evaluate the depression, indicating a ping-pong fracture. Computed tomography (CT) scan additionally demonstrated a small zone of contusion below the depression. Surgical elevation was opted because of this underlying contusion. A follow-up CT-scan was performed the day after surgery, which showed complete resolution of the depression and a small subarachnoid haemorrhage. The child was discharged home on day 7 with a normal neurological examination. Discussion: A ping-pong fracture is a type of fracture seen only in neonates and young infants. It consists of a depression of the skull without cortical break. These depressed skull fractures can either be congenital or acquired. Congenital depressions of the neonatal skull unrelated to trauma are rare and often puzzling in origin. They are referred to as “faulty fetal packing”, since they are caused by external pressure in utero, e.g. by a bony prominence of the maternal pelvis or spine. Non-traumatic, congenital depression fractures are the result of moulding of the soft foetal skull during its intra-uterine stay. Intra-cranial abnormalities are therefore rare. Acquired depressed skull fractures are more common and are usually caused by birth trauma due to obstetric manoeuvres or instrumental delivery. The acquired type of depressed fracture carries a higher risk of intra-cranial lesions, because of the sudden and important force applied to the skull. Management of ping-pong fractures in newborns is based on careful history taking and thorough clinical examination. A difficult delivery, e.g. with need for instrumentation, is more likely to cause traumatic ping-pong fractures and must always alert the clinician with respect to possible intra-cranial damage. Surgical lifting of the bone must be considered and was therefore applied in this case. A trouble-free birth without perinatal history for trauma and a newborn without neurological symptoms, is more likely a case of “faulty fetal packing”. This can be treated conservatively, as full and spontaneous resolution within the first few months of life has been described. Surgical correction is necessary when spontaneous resolution has not occurred by 6 months of age or when neurological symptoms appear

Improving take-up by reaching out to potential beneficiaries : insights from a large-scale field experiment in Belgium

Non-take-up of means-tested benefits is a widespread phenomenon which undermines the effectiveness and fairness of social policies. The digitalisation of the welfare state creates new opportunities for proactively contacting people who are potentially entitled to benefits, but do not take up their social rights. In this study, we report on how new data flows were used to reach out to potential beneficiaries of the Increased Reimbursement of health care, a programme targeted at low-income households in Belgium. By randomizing the period in which potential beneficiaries were contacted, we were able to identify a three- to four-fold increase in take-up among those contacted as a result of the outreaching activities. Households that did not respond to the intervention, the never takers, have lower pre-intervention healthcare expenditures. This suggests that non-take-up was reduced primarily among those who would expect to benefit most from receiving the Increased Reimbursement. Exploiting the combination of rich administrative data with experimental evidence, we also find that early responders are mostly older and have higher historic health expenditures than late responders. Furthermore, results point to the need for balancing well the inclusiveness of the intervention with an increased number of applications by ineligible people