Journal of Perinatology (2015), 1–6 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
ORIGINAL ARTICLE
Predictors of successful closure of patent ductus arteriosus with indomethacin MF Ahamed1, P Verma2,5, S Lee3,5, M Vega1, D Wang4, M Kim4 and M Fuloria1 OBJECTIVE: To determine whether platelet counts can predict the likelihood of successful closure of patent ductus arteriosus (PDA) with indomethacin. STUDY DESIGN: This was a retrospective cohort study of infants o32 weeks’ gestational age (GA) and birth weight o1500 g with PDA. Clinical characteristics between infants who achieved ductal closure with indomethacin and those who failed were compared. Multivariable logistic regression was used to identify predictors of successful ductal closure. RESULTS: In infants with hemodynamically significant PDA, older GA (odds ratio = 1.54; 95% confidence interval: 1.12 to 2.13), male gender (odds ratio = 3.02; 95% confidence interval: 1.08 to 8.49) and higher platelet count (odds ratio = 1.5; 95% confidence interval: 1.04 to 2.17) prior to indomethacin treatment were associated with successful ductal closure with indomethacin. CONCLUSION: Older GA, male gender and higher platelet count at time of treatment of hemodynamically significant PDA are predictors of successful ductal closure with indomethacin. Journal of Perinatology advance online publication, 9 April 2015; doi:10.1038/jp.2015.33
INTRODUCTION Persistent patency of the ductus arteriosus is a common problem in preterm infants. Normally, the ductus arteriosus undergoes functional closure within 48 h of life and completes anatomic closure over the next 2 to 3 weeks. In preterm infants, the ductus arteriosus may remain patent. There is a higher incidence of patent ductus arteriosus (PDA) with lower gestational age (GA) and birth weight (BW), with ~ 30% of infants o1500 g having a PDA.1 In infants o1000 g BW or o 28 weeks of gestation, ~ 50 to 70% may have a significant PDA necessitating either medical or surgical management.2 The presence of a PDA increases the risk of developing prematurity-related morbidities including respiratory failure, bronchopulmonary dysplasia (BPD), congestive heart failure, intraventricular hemorrhage (IVH), renal failure and necrotizing enterocolitis (NEC).3 In addition, the presence of a PDA has also been shown to be associated with an increased risk of mortality in preterm infants o29 weeks of gestation.4 Non-selective cyclooxygenase (COX) inhibitors such as ibuprofen and indomethacin are used for medical closure of the ductus; surgical ligation of the PDA is used either when there is failure of medical therapy or if there is a contraindication to the use of COX inhibitors. The use of COX inhibitors can be associated with adverse effects in preterm neonates, including oliguria, acute kidney injury and spontaneous intestinal perforation.5 Furthermore, COX inhibitors are ineffective in ductal closure in as many as 21 to 40% of preterm infants, with ~ 21% of infants with PDA requiring surgical ligation despite having received indomethacin.6–8 Maternal characteristics implicated in persistent ductal patency include lack of exposure to antenatal betamethasone, maternal race, pregnancy-induced hypertension and intrauterine inflam-
mation.8–10 Neonatal characteristics associated with persistence of the ductus include lower GA, respiratory distress syndrome and sepsis.5,8–12 Delayed initiation of treatment with indomethacin, larger ductal size and thrombocytopenia have been described in patients whose ductus failed to close with indomethacin treatment.6,13,14 Echtler et al.14 have shown that platelets are involved in functional closure as well as in subsequent remodeling and eventual fibrosis of the ductus in mouse pups. Interestingly, mice with defective platelet adhesion or biogenesis had high rates of persistent PDA, even after treatment with indomethacin, suggesting that an initial ductal constriction followed by occlusion of the residual ductal lumen with platelets is needed for ductal closure. Retrospective analyses indicate that thrombocytopenia is an independent predictor of both a PDA as well as a hemodynamically significant PDA.15,16 Whether thrombocytopenia is associated with failure of COX inhibitors in closing the ductus remains controversial. Boo et al.6 have shown that thrombocytopenia is a risk factor for the failure of medical therapy in closing PDA. In contrast, Dani has shown that although thrombocytopenia increases the risk of developing a hemodynamically significant PDA, it does not affect ductal closure rates with ibuprofen.16 Similarly, Fujioka et al.17 have shown no difference in the frequency of PDA closure in preterm neonates with thrombocytopenia. The primary objective of this study was to determine whether the platelet count at the time of medical treatment predicted successful ductal closure with indomethacin. Our secondary objectives were to identify maternal and neonatal factors associated with the success of ductal closure with indomethacin. We hypothesized that preterm infants with thrombocytopenia
1 Division of Neonatal-Perinatal Medicine, The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA; 2Division of Neonatology, Alpert Medical School of Brown University, Providence, RI, USA; 3Division of Pediatric Cardiology, Mount Sinai Hospital, Icahn School of Medicine, New York, NY, USA and 4Department of Epidemiology & Population Health, Division of Biostatistics, Albert Einstein College of Medicine, Bronx, NY, USA. Correspondence: Dr M Fuloria, Division of Neonatal-Perinatal Medicine, The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, 1601 Tenbroeck Avenue, 2nd Floor, Bronx 10461, NY, USA. E-mail: mfuloria@montefiore.org 5 These authors contributed equally to this work. Received 4 December 2014; revised 11 February 2015; accepted 2 March 2015
Patent ductus arteriosus and indomethacin MF Ahamed et al
2
(platelet count o150 × 103 μl − 1) at the time of indomethacin treatment will have an increased likelihood of not responding to medical therapy when compared with preterm infants with normal platelet counts.
Total number of admissions (
ORIGINAL ARTICLE
Predictors of successful closure of patent ductus arteriosus with indomethacin MF Ahamed1, P Verma2,5, S Lee3,5, M Vega1, D Wang4, M Kim4 and M Fuloria1 OBJECTIVE: To determine whether platelet counts can predict the likelihood of successful closure of patent ductus arteriosus (PDA) with indomethacin. STUDY DESIGN: This was a retrospective cohort study of infants o32 weeks’ gestational age (GA) and birth weight o1500 g with PDA. Clinical characteristics between infants who achieved ductal closure with indomethacin and those who failed were compared. Multivariable logistic regression was used to identify predictors of successful ductal closure. RESULTS: In infants with hemodynamically significant PDA, older GA (odds ratio = 1.54; 95% confidence interval: 1.12 to 2.13), male gender (odds ratio = 3.02; 95% confidence interval: 1.08 to 8.49) and higher platelet count (odds ratio = 1.5; 95% confidence interval: 1.04 to 2.17) prior to indomethacin treatment were associated with successful ductal closure with indomethacin. CONCLUSION: Older GA, male gender and higher platelet count at time of treatment of hemodynamically significant PDA are predictors of successful ductal closure with indomethacin. Journal of Perinatology advance online publication, 9 April 2015; doi:10.1038/jp.2015.33
INTRODUCTION Persistent patency of the ductus arteriosus is a common problem in preterm infants. Normally, the ductus arteriosus undergoes functional closure within 48 h of life and completes anatomic closure over the next 2 to 3 weeks. In preterm infants, the ductus arteriosus may remain patent. There is a higher incidence of patent ductus arteriosus (PDA) with lower gestational age (GA) and birth weight (BW), with ~ 30% of infants o1500 g having a PDA.1 In infants o1000 g BW or o 28 weeks of gestation, ~ 50 to 70% may have a significant PDA necessitating either medical or surgical management.2 The presence of a PDA increases the risk of developing prematurity-related morbidities including respiratory failure, bronchopulmonary dysplasia (BPD), congestive heart failure, intraventricular hemorrhage (IVH), renal failure and necrotizing enterocolitis (NEC).3 In addition, the presence of a PDA has also been shown to be associated with an increased risk of mortality in preterm infants o29 weeks of gestation.4 Non-selective cyclooxygenase (COX) inhibitors such as ibuprofen and indomethacin are used for medical closure of the ductus; surgical ligation of the PDA is used either when there is failure of medical therapy or if there is a contraindication to the use of COX inhibitors. The use of COX inhibitors can be associated with adverse effects in preterm neonates, including oliguria, acute kidney injury and spontaneous intestinal perforation.5 Furthermore, COX inhibitors are ineffective in ductal closure in as many as 21 to 40% of preterm infants, with ~ 21% of infants with PDA requiring surgical ligation despite having received indomethacin.6–8 Maternal characteristics implicated in persistent ductal patency include lack of exposure to antenatal betamethasone, maternal race, pregnancy-induced hypertension and intrauterine inflam-
mation.8–10 Neonatal characteristics associated with persistence of the ductus include lower GA, respiratory distress syndrome and sepsis.5,8–12 Delayed initiation of treatment with indomethacin, larger ductal size and thrombocytopenia have been described in patients whose ductus failed to close with indomethacin treatment.6,13,14 Echtler et al.14 have shown that platelets are involved in functional closure as well as in subsequent remodeling and eventual fibrosis of the ductus in mouse pups. Interestingly, mice with defective platelet adhesion or biogenesis had high rates of persistent PDA, even after treatment with indomethacin, suggesting that an initial ductal constriction followed by occlusion of the residual ductal lumen with platelets is needed for ductal closure. Retrospective analyses indicate that thrombocytopenia is an independent predictor of both a PDA as well as a hemodynamically significant PDA.15,16 Whether thrombocytopenia is associated with failure of COX inhibitors in closing the ductus remains controversial. Boo et al.6 have shown that thrombocytopenia is a risk factor for the failure of medical therapy in closing PDA. In contrast, Dani has shown that although thrombocytopenia increases the risk of developing a hemodynamically significant PDA, it does not affect ductal closure rates with ibuprofen.16 Similarly, Fujioka et al.17 have shown no difference in the frequency of PDA closure in preterm neonates with thrombocytopenia. The primary objective of this study was to determine whether the platelet count at the time of medical treatment predicted successful ductal closure with indomethacin. Our secondary objectives were to identify maternal and neonatal factors associated with the success of ductal closure with indomethacin. We hypothesized that preterm infants with thrombocytopenia
1 Division of Neonatal-Perinatal Medicine, The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA; 2Division of Neonatology, Alpert Medical School of Brown University, Providence, RI, USA; 3Division of Pediatric Cardiology, Mount Sinai Hospital, Icahn School of Medicine, New York, NY, USA and 4Department of Epidemiology & Population Health, Division of Biostatistics, Albert Einstein College of Medicine, Bronx, NY, USA. Correspondence: Dr M Fuloria, Division of Neonatal-Perinatal Medicine, The Children’s Hospital at Montefiore, Albert Einstein College of Medicine, 1601 Tenbroeck Avenue, 2nd Floor, Bronx 10461, NY, USA. E-mail: mfuloria@montefiore.org 5 These authors contributed equally to this work. Received 4 December 2014; revised 11 February 2015; accepted 2 March 2015
Patent ductus arteriosus and indomethacin MF Ahamed et al
2
(platelet count o150 × 103 μl − 1) at the time of indomethacin treatment will have an increased likelihood of not responding to medical therapy when compared with preterm infants with normal platelet counts.
Total number of admissions (
