Prophylaxis for patent ductus arteriosus in preterm infant

One of the most important modifications which takes place after birth is the closure of the ductus arteriosus and the consequent division of the pulmonary artery from the aorta. This remodelling usually occurs within 48 hours after birth, but if the ductus fails to close within 72 hours a persistent patent ductus arteriosus (PDA) is diagnosed.

Patent ductus arteriosus is a significant health risk to preterm babies. The PDA determines an increase of cardiac output and pulmonary blood pressure and a decrease of the blood flow to the rest of the organism. Consequently to this altered redistribution of blood flow, the blood pressure dramatically drops. Furthermore, the PDA may lead to severe neonatal morbidities, i.e. intracranial hemorrhage, pulmonary edema/hemorrhage, necrotizing enterocolitis (NEC) and metabolic acidosis.

In full-term infants, the closure of the ductus arteriosus is a two step process: i) the ductus lumen constricts in response to the higher systemic arterial oxygen tension (PaO 2) and to the lower level of circulating prostaglandins (PGs); ii) as a result of the lumen constriction, the inner muscle walls of the ductus develop an ischemic hypoxia with a consequent release of inflammatory mediators and growth factors, which transform the ductus in a non-contractile ligament.

In preterm infants these two steps are frequently hindered. The reason for this has to be ascribed firstly to a little contractile capability of the premature ductus. Moreover, even if the ductus successfully contracts, it remains frequently resistant to the hypoxic ischemia. This resistance is due to its large lumen and its thin muscle walls, which are easily reachable by the nutrient flow, even if the vessel is contracted. As a result, if the hypoxic ischemia necessary for the permanent tissue remodelling is not elicited, the arteriosus ductus can eventually reopen.

The treatment of PDA requires pharmacological therapy or, in the most serious cases, surgical intervention (i.e. the ligation of the ductus). The pharmacological treatment is principally based on the use of indomethacin, a prostaglandin inhibitor, which has been utilized both for the symptomatic phase treatment as well as for the prevention of PAD. There is still ongoing debate about the prophylactic use of indomethacin in preterm infant. The major concerns are about the administration of a drug which might reveal to be unnecessary. On the other hand, clinical experience reveals that without a prophylactic therapy, 55%-70% of the newborns delivered below 1000 g or prior to 28 weeks of gestation ultimately will develop PDA during their hospitalization. Furthermore, preterm infants who receive prophylactic therapy with PG inhibitors within 6-15 hours after their birth, have minor incidence of morbidities associated with PDA and a lower need for ductus ligation. In addition, clinical observations reveal that a treatment with PG inhibitors becomes less effective as postnatal age increases. This could be due to the presence of vasodilatory mediators, different from the PGs, which are released because of the inflammatory response that develops within the ductus shortly after birth.

Although a proper therapeutical approach to counteract the PDA in the premature babies has still to be validated, some positive effects can be obtained with a prophylactic protocol based on the use of PGs inhibitors. However, further clinical trials are needed to determine the ideal treatment parameters and timing.

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