Patent Ductus Arteriosus: Evidence for and against Treatment

Abstract

Numerous studies have shown that a prolonged, persistent left-to-right shunt through a patent ductus arteriosus (PDA) shortens the life span of animals and humans(1–4). In preterm infants, a persistent PDA is due in large part to alterations in prostaglandin metabolism. Inhibition of prostaglandin production with indomethacin has been the mainstay of preterm PDA treatment since the mid 1970’s (5). In recent years there has been a growing debate about whether or not to treat a persistent PDA during the neonatal period(6). Preterm infants have a high rate of spontaneous PDA closure during the first 2 years. Therefore, early treatment runs the risk of exposing infants to drugs or procedures they might not need. In this issue of The Journal, the report by Kabra et al(7) fans the flames of this controversy. In the following review, we will examine the evidence for and against PDA treatment during the neonatal period. Although a persistent PDA is associated with several important neonatal morbidities, its role in causing these morbidities is currently in question (6). Based on existing clinical trials, it is hard to tell whether the reported association between a persistent PDA and other neonatal morbidities is due to the left-to-right PDA shunt itself, the therapies used to treat it, or the immaturity of the infant that is likely to develop a PDA. Only one randomized, controlled trial, performed more than 25 years ago, was designed specifically to examine the role of a persistent untreated PDA in neonatal morbidity(8). The investigators found that a persistent PDA increased pulmonary morbidity and prolonged the need for respiratory support. The trial size was too small to examine the PDA’s effect on other neonatal morbidities. Unfortunately, the vast majority of PDA treatment trials were never designed to examine the role of a persistent PDA in neonatal morbidity; they were designed to assess the relationship between “timing,” or initiation, of treatment and efficiency of PDA closure. All of the trials utilized “back up treatments” to close the PDA if it persisted beyond several days. These “timing” trials can give us information about the role of a PDA in producing morbidity, only if the morbidity’s appearance and/or underlying cause occur during the period of PDA exposure (between the initial and back up treatments) (Figure). On the other hand, these trials tell us nothing about the role of the PDA in morbidities that occur after infants have received their back up treatment, or in morbidities that occur before the trial begins (Figure). Figure Relationship between treatment times in randomized PDA trials and the occurrence of common neonatal morbidities. Each trial type (Prophylactic or Symptomatic) entered infants into an Initial Early treatment or Control (no treatment) group. Several days ... What information can be gleaned from these “timing” trials? There are basically two types of “timing” trials: Prophylactic (where treatment starts within 24 hours of birth) and Symptomatic (where treatment starts when symptoms appear: start times are usually between 2 and 7 days after birth).