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BackgroundMuch controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking.MethodsThis multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis.DiscussionAs a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks.Trial registrationThis trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017–001376-28.

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Cardiorespiratory function is not only the foremost determinant of life after premature birth, but also a major factor of long-term outcomes. However, the path from placental disconnection to nutritional autonomy is enduring and challenging for the preterm infant and, at each step, will have profound influences on respiratory physiology and disease. Fluid and energy intake, specific nutrients such as amino-acids, lipids and vitamins, and their ways of administration —parenteral or enteral—have direct implications on lung tissue composition and cellular functions, thus affect lung development and homeostasis and contributing to acute and chronic respiratory disorders. In addition, metabolomic signatures have recently emerged as biomarkers of bronchopulmonary dysplasia and other neonatal diseases, suggesting a profound implication of specific metabolites such as amino-acids, acylcarnitine and fatty acids in lung injury and repair, inflammation and immune modulation. Recent advances have highlighted the profound influence of the microbiome on many short- and long-term outcomes in the preterm infant. Lung and intestinal microbiomes are deeply intricated, and nutrition plays a prominent role in their establishment and regulation. There is an emerging evidence that human milk prevents bronchopulmonary dysplasia in premature infants, potentially through microbiome composition and/or inflammation modulation. Restoring antibiotic therapy-mediated microbiome disruption is another potentially beneficial action of human milk, which can be in part emulated by pre- and probiotics and supplements. This review will explore the many facets of the gut-lung axis and its pathophysiology in acute and chronic respiratory disorders of the prematurely born infant, and explore established and innovative nutritional approaches for prevention and treatment.

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