Multiple Courses of Indomethacin and Neonatal Outcomes in Premature Infants

Abstract

The objective of this retrospective cohort study was to determine patent ductus arteriosus (PDA) closure rate with multiple short courses (three doses) of postnatal indomethacin and compare neonatal outcomes in infants who received two versus three courses of indomethacin for PDA closure. Infants <34 weeks' gestational age born between January 2000 and December 2004 at the University of Maryland Medical Center and who received two or more short courses of indomethacin were included. Outcome measures were ductal closure rate and neonatal outcomes. Of 61 infants who were identified to have received two or more courses of indomethacin, 26 infants closed their ductus after the second course (response rate, 42%). Of the 35 infants who failed ductal closure after two courses, 11 infants had their ductus ligated and 23 received a third course of indomethacin. Of 23 who received a third course, 10 closed their ductus (response rate, 43%). There was no significant difference in the incidence of chronic lung disease, severe retinopathy of prematurity, necrotizing enterocolitis, renal function, or mortality between infants who received two and those who received three courses of indomethacin. Infants exposed to three courses of indo-methacin had a statistically nonsignificant increased incidence of periventricular leukomalacia (p = 0.08; adjusted odds ratio = 4.8; 95% CI, 0.8-30) and remained in the hospital for a longer duration (p = 0.02) compared to infants exposed to two courses of indomethacin. We conclude that multiple courses of indomethacin may be associated with a ductal closure. However, the requirement for a third course may be associated with an increased risk of periventricular leukomalacia. Indomethacin, a potent inhibitor of prostaglandin synthesis, has been routinely used to treat patent ductus arteriosus (PDA) in premature infants [10,28]. However, approximately 20%-40% of premature infants have residual luminal flow or fail to close after the initial short course (three doses given every 12 h) of indomethacin [4,12,15,28]. If the ductus fails to close after the initial course of indomethacin, surgical ligation of PDA and additional indomethacin treatment are two available options for the management of persistent PDA [20,24]. It is not clear whether surgical ligation or multiple courses of indo-methacin should be the preferred treatment of PDA that fails to close after the initial short course of indomethacin [7,19,25]. The medical literature suggests that additional indomethacin treatment is unlikely to produce ductus closure for premature infants, if there is persistent Doppler evidence of ductal flow within 24 h after completion of the initial short course of indomethacin [17]. Contrary to this limited evidence, a recent survey of Neonatal Fellowship Program Directors in the United States reported that multiple courses of indomethacin, up to three, are commonly used for persistent PDA, after the initial course of indo-methacin [1]. This survey also reported that there is wide variation in the ma...

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“…The degree of hypoxia and its duration are all important when considering possible tissue damage. A recent study by Sangem et al [16] showed an increase in periventricular leukomalacia associated with repeated courses of indomethacin. This could be explained by the effect of indomethacin on the cerebral blood flow discussed earlier.…”

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“…But in the same study a higher incidence of periventricular leucomalacia was noted in those receiving the third course. This may be due to the well‐established vasoconstrictive effects of indomethacin, or the results may well have been confounded by the cohort of sicker neonates with associated comorbidities who failed to respond to the first two courses …”

Controversies in Management of Patent Ductus Arterious in the Preterm Infant

“…However, a higher increase of periventricular leukomalacia in those who received a 3 rd course of indomethacin does raise some concern. Like Indomethacin, the closure rate of PDA after a second or third course of ibuprofen was similar to the closure rate after the first course but not associated with an increase in adverse effects [54].…”

“…In a retrospective study, Sangem et al [53,54] observed a 42% response rate after a second course of indomethacin and a 43%, with the third course of indomethacin, yielding a cumulative response rate to 3 courses of indomethacin of 90%. However, a higher increase of periventricular leukomalacia in those who received a 3 rd course of indomethacin does raise some concern.…”