Predictors of successful closure of patent ductus arteriosus with indomethacin

Subjects

Abstract

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 <32 weeks’ gestational age (GA) and birth weight <1500 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.

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 <1500 g having a PDA.1 In infants <1000 g BW or <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 <29 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, 7, 8

Maternal characteristics implicated in persistent ductal patency include lack of exposure to antenatal betamethasone, maternal race, pregnancy-induced hypertension and intrauterine inflammation.8, 9, 10 Neonatal characteristics associated with persistence of the ductus include lower GA, respiratory distress syndrome and sepsis.5, 8, 9, 10, 11, 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 (platelet count <150 × 103μl−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.

Methods

This was an observational, retrospective cohort study of all infants with GA <32 weeks and BW <1500 g who were admitted to the Neonatal Intensive Care Unit at the Children’s Hospital at Montefiore, Weiler Division, from 2005 to 2012 and were diagnosed to have a PDA. Eligible infants were identified from our comprehensive neonatal database. Infants were excluded from the study if they met the following criteria: (1) presence of congenital anomalies involving the cardiovascular system or any other major malformations, (2) congenital viral infections or (3) transfer from a referring institution. The presence of congenital anomalies and viral infections was determined by reviewing the charted diagnosis for each infant.

Baseline maternal and neonatal demographic information were abstracted from our database and medical record review. Maternal characteristics analyzed included age, race, mode of delivery, antenatal steroid administration and the presence/absence of hypertension and gestational diabetes. Neonatal characteristics recorded included GA, BW, gender, race, small for gestational age status, and Apgar score 5 at 5 min of life. Additional neonatal characteristics analyzed included clinical risk index for babies (CRIB) scores as an indicator of illness severity in the first 12 h of life, presence of PDA with or without the need for surgical ligation, presence and severity of BPD, NEC, gastrointestinal perforation, severity of IVH and average fluid intake over the first 2 weeks of life. The platelet count on the first day of life and prior to administration of indomethacin were recorded in all infants. Thrombocytopenia was defined as platelet count <150 × 103μl−1.

Infants with PDA were categorized as: (1) neonates with PDA that were not hemodynamically significant and/or closed spontaneously; (2) neonates who received indomethacin therapy for medical management of the PDA; and (3) neonates who underwent primary surgical ligation for PDA. Neonates who received indomethacin were further categorized as: (1) neonates who achieved ductal closure with indomethacin alone (that is, medical management); and (2) neonates who failed indomethacin treatment and subsequently required surgical ligation. The PDA was defined as hemodynamically significant if it met at least two of the following three criteria on echocardiography: (1) size >1.4mm; (2) left atrial enlargement and (3) diastolic reversal of blood flow in the abdominal aorta.

Data analysis

Clinical characteristics of infants in the three groups were described using standard summary statistics including the mean, s.d. and frequencies. Characteristics of infants who achieved ductal closure using indomethacin were compared with those who failed indomethacin treatment using Fisher’s exact test for categorical variables and t-test for continuous variables. Multivariable logistic regression was used to identify independent predictors of successful ductal closure using indomethacin. Given that platelet count was the primary predictor of interest, this variable was included in the final logistic regression model along with any other covariates that were either statistically significant and/or changed the coefficient for platelet count by >20%. P-value of <0.05 was considered statistically significant. All analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA).

Results

A total of 833 preterm infants with GA <32 weeks and BW <1500 g were admitted to the Neonatal Intensive Care Unit at the Children’s Hospital at Montefiore, Weiler Division, from 2005 to 2012. Of these, 203 infants (24.3%) were found to have a PDA and thus were eligible for the study; 181 of these infants (89.2%) required treatment for the ductus (Figure 1). Of the infants requiring treatment, 62 (34.3%) underwent primary surgical ligation of the ductus owing to contraindications for indomethacin treatment (Grade 3 or 4 IVH, NEC, bowel perforation or renal dysfunction). One hundred and nineteen infants (65.7%) received medical treatment with indomethacin and were included for further analysis.

Figure 1
figure1

Study population. Flow chart depicts the total number of admissions meeting eligibility criteria in the study period and distribution of infants with PDA and type of therapy required. Numbers are the total number of infants with percentages in parenthesis.

Clinical characteristics of all infants with PDA

Baseline characteristics of all infants with PDA are described in Table 1. There was no difference in the mode of delivery or the presence of maternal morbidities, such as hypertension and gestational diabetes, between the three groups. Infants with PDA who required either medical or surgical treatment had lower GA and BW as compared with those who did not require any treatment (P<0.001). The presence of a hemodynamically significant PDA was associated with an increased likelihood of either medical or surgical treatment of the ductus (P<0.001). Furthermore, infants whose PDA was treated with either indomethacin or surgical ligation were sicker as evidenced by higher CRIB scores (P<0.001) and a higher incidence of prematurity-related morbidities such as respiratory distress syndrome (P=0.014), BPD (P<0.001), IVH (P<0.001), periventricular leukomalacia (P=0.006) and retinopathy of prematurity (ROP) (P<0.001).

Table 1 Clinical characteristics of all infants <32 weeks’ GA and <1500 g BW with PDA

Clinical characteristics of all infants with PDA who were treated with indomethacin

As shown in Table 2, male infants and those born by cesarean section were more likely to have successful closure of the PDA with indomethacin. There was no statistical difference in the rates of exposure to antenatal steroids or maternal gestational diabetes between the two groups; however, mothers of infants who were successfully treated with indomethacin were more likely to have gestational hypertension (P=0.006). Infants with older GA (26.9±1.7 weeks vs 25.5±1.5 weeks; P<0.001), higher BW (869.3±187.7 g vs 774.4±206.2 g; P=0.015), and lower CRIB scores (10.7±2.7 vs 12.5±2.6; P<0.001) were more likely to be successfully treated with indomethacin. Infants who were successfully managed with medical therapy also received lower total fluids on the days prior to initiation of indomethacin treatment as compared with infants who failed medical management (141.1±21.9 ml kg−1 per day vs 158.9±29.8 ml kg−1 per day; P<0.001). The mean platelet count within the first 24 hours of life did not affect the likelihood of successful treatment of PDA with indomethacin. The mean platelet count at the time of indomethacin treatment was higher in infants who were successfully treated with medical therapy as compared with those infants who failed medical management (214.7±95.3 x 103μl−1 vs 179.3±67.9 x 103μl−1; P=0.024). The change in platelet count between day of life 1 and the start of indomethacin treatment did not affect the likelihood of success of medical therapy in patients with a PDA (P=0.709). In a multivariate logistic regression analysis, male gender, increasing GA, absence of a hemodynamically significant PDA and lower total fluid intake prior to initiation of indomethacin treatment were associated with successful closure of the ductus with indomethacin (Table 3).

Table 2 Clinical characteristics of all infants with PDA who received indomethacin treatment
Table 3 Logistic regression model for successful treatment with indomethacin

Clinical characteristics of infants with hemodynamically significant PDA who were treated with indomethacin

A total of 86 infants (47.5% of those that required treatment) had a hemodynamically significant PDA. As shown in Table 4, delivery via cesarean section (P=0.001), male gender (P=0.037) and the presence of maternal hypertension (P<0.001) were associated with successful ductal closure with indomethacin. Successful medical therapy was associated with older GA (27.1±1.7 weeks vs 25.6±1.6 weeks; P<0.001), lower CRIB scores (10.4±2.5 vs 12.3±2.6; P=0.001) and lower fluid intake prior to initiation of indomethacin treatment (138.4±18.2 ml kg−1 per day vs 153.1±26.7 ml kg−1 per day; P=0.009). There was no difference in the mean platelet count at the time of indomethacin treatment in infants who were successfully treated with indomethacin as compared with those who failed indomethacin treatment (219.5±97.4 × 103μl−1 vs 184.0±72 × 103 μl−1; P=0.079). Similarly, the change in platelet count between day of life one and the start of indomethacin treatment did not affect the likelihood of successful PDA treatment with indomethacin (P=0.740). The average number of doses of indomethacin received and the day of life when indomethacin therapy was initiated was comparable between the two groups. In a multivariable logistic regression analysis, male gender, maternal hypertension and higher platelet count at the time of indomethacin treatment were predictive of successful closure of a hemodynamically significant PDA with indomethacin (Table 5).

Table 4 Clinical characteristics of infants with a hemodynamically significant PDA who received indomethacin treatment
Table 5 Logistic regression model for successful treatment with indomethacin in infants with hemodynamically significant PDA

Discussion

The presence of a PDA in preterm infants is associated with significant neonatal morbidity and mortality. Although COX inhibitors (indomethacin or ibuprofen) are routinely used for medical closure of the PDA in a select group of neonates, there is a high rate of unsuccessful medical therapy, with reported failure rates as high as 21 to 40%.6, 7, 8 Similar to previous reports, we observed that 30% of patients in our cohort with a PDA who were treated with indomethacin failed medical management and subsequently required surgical ligation (Figure 1). The incidence of PDA in our cohort is also similar to that observed by Fujioka (24% in our cohort vs 30% in the Fujioka cohort) but significantly lower than seen in the Sallmon study (70% incidence of PDA). Consistent with previously published reports, our data demonstrate that infants with PDA who achieve ductal closure with indomethacin therapy have higher gestational age and are less likely to have a hemodynamically significant PDA when compared with infants who are unsuccessfully treated with indomethacin.6, 8, 10, 18, 19

The association between thrombocytopenia and failure of medical therapy for PDA remains controversial. Although Ecthler has shown a clear association between platelet count and ductal closure in mouse pups, the association between platelet counts and successful ductal closure in other animal models and preterm neonates remains unclear. Other pathways implicated in ductal patency and closure in experimental models and humans include decreased expression/function of calcium and potassium channels, CD14+/CD163+ mononuclear cell adhesion to the ductal lumen (for neointimal growth), and isoprostane-mediated signaling via EP4 receptors.20, 21, 22, 23 Candidate gene studies have identified specific gene polymorphisms associated with PDA in human preterm infants, with polymorphisms in the TFAP2B and TNF receptor-associated factor 1 genes reported to be associated with the presence of a PDA.20

Previously published reports have primarily focused on the platelet counts during the first few days of life. Our study differs from others in that we also investigated the platelet count at the time of initiation of indomethacin therapy as a possible predictor of the success of medical management. In our cohort of racially diverse preterm infants, we did not find a relationship between platelet count either on the first day of life or at the time of treatment with indomethacin and subsequent successful closure of the ductus with indomethacin. Interestingly, in infants who had a hemodynamically significant PDA, there was a 1.5-fold increased likelihood of successful medical therapy in the presence of higher platelet counts (Table 5). Several studies have evaluated the association between platelet counts during the first 3 days of life and the success of medical management in closing the PDA. Echtler et al.14 previously reported that thrombocytopenia in the first day of life, defined as a platelet count <150 X 103 μl−1, was associated with failure of indomethacin therapy. Furthermore, they observed that thrombocytopenia was an independent risk factor for a PDA with hemodynamic relevance. Similarly, in larger preterm infants (<37 weeks’ GA and with BW <1750 g), lower platelet counts were predictive of failed closure of PDA with indomethacin.6 In contrast, in a cohort of preterm infants between 24 to 30 weeks GA, Fujioka et al.17 observed no association between thrombocytopenia and PDA closure with indomethacin. Similarly, Sallmon et al.18 showed that thrombocytopenia in the first 24 h of life was not associated with a clinically significant PDA. Shah et al.19 recently published the only prospective study looking at a large cohort of preterm infants <28 weeks of gestation managed with an aggressive protocol including prophylactic indomethacin. Prospective analyses showed that persistence of a PDA was not related to platelet count at any time during the first week of life. Unlike previous studies, which only evaluated platelet counts in the first 3 days of life, this study examined platelet counts over the first week of life, the time period in which constriction is most likely to occur in human infants. Their findings conflict with the Echtler model, which suggests that platelets accumulate in and contribute to obliteration of the already constricted ductal lumen, promoting permanent anatomic closure.14 One possibility is that lower platelet counts may be a surrogate marker for the severity of illness in preterm infants who are at higher risk of ductal patency as well as failure of pharmacologic treatment. The findings in our cohort are consistent with this hypothesis as infants who failed to close their ductus with indomethacin were sicker as evidenced by higher CRIB scores, lower BW and GA and an increased incidence of prematurity-related morbidities such as IVH and retinopathy of prematurity.

Interestingly, male gender significantly improved the odds of successful medical treatment (Tables 3 and 5). To our knowledge, this is the first report describing gender differences in ductal closure with indomethacin therapy. The incidence of PDA has previously been reported to be higher in females.24 It is possible that there is a sexually dimorphic developmental difference in the prostaglandin responsiveness of the ductal tissue that may prevent spontaneous closure of the ductus in females; alternatively, there may be gender differences in the degree of inhibition of prostaglandin by COX inhibitors that may explain these findings. Further studies are needed to explore these gender-based differential responses to indomethacin.

Gestational hypertension was associated with successful closure of ductus with indomethacin. In infants with a hemodynamically significant PDA, this was found to be an independent predictor of the success of closure of the ductus with medical therapy alone. This finding is consistent with previous studies in which gestational hypertension has been shown to be an independent predictor of spontaneous closure of ductus.9 This may be secondary to decreased ductal flow from elevated placental resistance in mothers with gestational hypertension.

It has previously been shown that increased fluid intake during the first 3 days of life is an independent risk factor for the presence of PDA.25 In our study, we observed that the mean fluid intake prior to the initiation of indomethacin was significantly lower in infants with PDA who responded successfully to indomethacin therapy (Table 3). This finding may be related to the hemodynamic instability that is often observed in preterm infants with PDA and may be secondary to the left to right shunting across the ductus. After controlling for confounding factors, this finding persisted with lower odds of failure of indomethacin therapy with lower mean fluid intake.

In conclusion, we did not find an association between thrombocytopenia at the time of treatment of PDA and failure of medical treatment in achieving ductal closure. However, in infants with a hemodynamically significant PDA, a higher platelet count at the time of indomethacin treatment was a predictor of successful ductal closure. Furthermore, we observed that males had an increased rate of ductal closure with indomethacin, suggesting that there may be sexually dimorphic developmental differences in ductal tissue responsiveness to indomethacin. Higher GA and lower mean fluid intake at the time of initiation of indomethacin treatment were also associated with successful closure of the ductus with indomethacin.

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Correspondence to M Fuloria.

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Author Contributions

Mohamed Farooq Ahamed: Dr Ahamed was responsible for acquisition of the data, analysis and interpretation of the data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Prasoon Verma: Dr Verma was responsible for acquisition of data. Drs Verma and Lee contributed equally to the manuscript. Simon Lee: Dr Lee was responsible for the study concept, acquisition of data and revision of the manuscript. Dan Wang: Ms. Wang was responsible for analysis and interpretation of the data, statistical analysis and revision of the manuscript for important intellectual content. Mimi Kim: Dr Kim was responsible for analysis and interpretation of the data, statistical analysis and critical revision of the manuscript for important intellectual content. Melissa Vega: Ms Vega was responsible for acquisition of the data and administrative, technical and material support. Mamta Fuloria: Dr Fuloria was responsible for the study concept and design, acquisition of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content and study supervision.

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Ahamed, M., Verma, P., Lee, S. et al. Predictors of successful closure of patent ductus arteriosus with indomethacin. J Perinatol 35, 729–734 (2015). https://doi.org/10.1038/jp.2015.33

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