Published online June 1, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. 1165-1174 (doi:10.1542/peds.2006-3124)
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ARTICLE

Patent Ductus Arteriosus and Its Treatment as Risk Factors for Neonatal and Neurodevelopmental Morbidity

Nancy Chorne, MDa, Carol Leonard, PhDa, Robert Piecuch, MDa and Ronald I. Clyman, MDa,b

a Department of Pediatrics
b Cardiovascular Research Institute, University of California, San Francisco, California


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. The purpose of this work was to determine whether the reported association between neonatal morbidities and a patent ductus arteriosus is because of the left-to-right patent ductus arteriosus shunt itself, the therapies used to treat it, or the immaturity of the infants who are likely to develop a patent ductus arteriosus.

METHODS. A total of 446 infants (<28 weeks' gestation) were treated with the same patent ductus arteriosus care–oriented protocol, and logistic regression analysis was used to examine the effects of several patent ductus arteriosus–related variables (presence of a symptomatic patent ductus arteriosus, the number of indomethacin doses used, the ductus response to indomethacin, and the use of surgical ligation) on the incidence of retinopathy of prematurity, necrotizing enterocolitis, chronic lung disease, death, and neurodevelopmental impairment.

RESULTS. Most of the predictive effects that the presence of a patent ductus arteriosus and its treatment had on neonatal morbidity could be accounted for by the infants' immature gestation. Use of surgical ligation, however, was significantly associated with the development of chronic lung disease and was independent of immature gestation, other patent ductus arteriosus–related variables, or other perinatal and neonatal risk factors known to be associated with chronic lung disease.

CONCLUSIONS. These findings add to the growing uncertainty about the benefits and risks of surgical ligation during the neonatal period.

Key Words: patent ductus arteriosus • indomethacin • surgical ligation • chronic lung disease • necrotizing enterocolitis • retinopathy of prematurity • neurodevelopmental outcome • cognitive outcome • neurologic abnormality

Abbreviations: PDA—patent ductus arteriosus • NEC—necrotizing enterocolitis • CLD—chronic lung disease • ROP—retinopathy of prematurity • ICH—intracranial hemorrhage • MDI—Mental Development Index • FSIQ—full-scale IQ • OR—odds ratio

The presence of a persistent left-to-right shunt through a patent ductus arteriosus (PDA) is associated with the development of other neonatal morbidities. At this time it is unclear whether the reported association between a persistent PDA and other neonatal morbidities is because of the left-to-right PDA shunt itself, the therapies used to treat it, or the immaturity of the infant who is likely to develop it.1,2 Most studies examining this issue have looked only at individual aspects of PDA-oriented care on neonatal morbidity (eg, the presence of a PDA by itself [without regard for size of shunt or treatments used],3–6 duration of exposure to a symptomatic PDA,7,8 use of indomethacin,9,10 timing of indomethacin treatment,11–14 duration of indomethacin treatment,15,16 ductus response to indomethacin treatment,17,18 and use of surgical ligation19–21). Few have considered all of the variables together when determining the effect of a PDA or its therapies on neonatal morbidity.

In the following study, we used a cohort of infants (<28 weeks' gestation) who were managed with a defined PDA care–oriented protocol in a single medical center to examine the effects of several aspects of PDA-oriented care on neonatal morbidity. We used multiple logistic regression modeling to determine which aspects of PDA-oriented care were most closely associated with the development of other neonatal morbidities.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Population and PDA Treatment Protocol
This project was approved by the institutional review board of the University of California San Francisco. Between January 1994 and July 2005, all of the infants <28 weeks' gestation, admitted within 15 hours of birth to the William H. Tooley Nursery at University of California San Francisco, were treated according to the following PDA care–oriented protocol. Infants received either a short 3-dose course of prophylactic indomethacin (0.2, 0.1, and 0.1 mg/kg, administered at 24-hour intervals) or an extended 6-dose course (0.2, 0.1, 0.1, 0.1, 0.1, and 0.1 mg/kg, at 24-hour intervals) starting within 15 hours of birth. A Doppler examination was performed after the second dose. If there was no evidence of ductus patency on the Doppler examination, infants received the short 3-dose course (prophylactic indomethacin was stopped after the third dose). If there was any evidence of ductus patency on the examination, infants received the extended 6-dose course. A repeat echo-Doppler examination was performed 24 to 36 hours after the last dose to determine the ductus response to prophylactic indomethacin.

After the prophylactic treatment, infants were examined daily for the appearance of clinical symptoms indicative of a PDA (systolic murmur, widened pulse pressure, and hyperdynamic precordium). If any of these occurred, an echo-Doppler examination was performed within 24 hours. If there was left-to-right flow through the PDA, the infant was considered to have a symptomatic PDA. The degree of left-to-right shunt was considered to be small or moderate on the basis of the absence or presence of holodiastolic retrograde flow in the descending aorta (at the level of the diaphragm).22 When infants developed a symptomatic PDA, they were treated with a 3-dose course of indomethacin (0.2, 0.1, and 0.1 mg/kg administered at 0, 12, and 36 hours) and/or ligation. The need for treatment did not depend on the need for respiratory support or the degree of left-to-right shunt. Even infants who required only nasal cannula oxygen received treatment if the ductus was patent on echo-Doppler examination.

The choice of which treatment (indomethacin or surgery) to initiate first for the symptomatic PDA was left to the attending neonatologist. The decision to use surgery, rather than indomethacin, was based mainly on the ductus response to the initial prophylactic indomethacin course,23 not on the infant's medical condition. Infants who closed their PDA after prophylactic indomethacin (by echo/Doppler) were more likely to be treated with a second 3-dose course of indomethacin if a symptomatic PDA developed; those who still had evidence of Doppler flow, after the course of prophylactic indomethacin, were more likely to be sent directly to surgery if the PDA became symptomatic.23 The infant's medical condition sometimes played a role in the treatment choice. Indomethacin was more likely to be used, as a first-line therapy, if infants were unstable when their symptomatic PDA presented; surgery was preferred for more stable infants. Eighteen percent of symptomatic PDAs were treated with indomethacin alone, 13% with ligation alone, and 69% with indomethacin and ligation. The age of presentation of symptomatic PDAs that were treated with indomethacin (15 ± 7 days [mean ± SD]) was not different from those that were treated with surgery (14 ± 8 days). All of the symptomatic PDAs were closed, pharmacologically and/or surgically, within 5 days of presentation. The duration of exposure to a symptomatic PDA, the interval between symptomatic PDA presentation and the start of indomethacin treatment, was 0.8 ± 1.3 days (mean ± SD; an echo to document closure was performed 2 days later). The interval between symptomatic PDA presentation and ligation was 1.9 ± 1.2 days (mean ± SD). This approach to PDA-oriented care was based on a review of the randomized, controlled trials that examined the relative effectiveness and morbidities of indomethacin prophylaxis11 and of prolonged exposure to a symptomatic PDA.7,8

Risk Factors and Outcome Variables
The perinatal and neonatal characteristics of this population are listed in Table 1. Gestational age was determined by the date of last menstrual period and early ultrasounds (before 24 weeks' gestation). If there were discrepancies, the early ultrasound dating was used. Necrotizing enterocolitis (NEC) was defined as Bell classification II or greater (this included NEC that was treated medically or surgically and so-called "spontaneous perforations").24 Chronic lung disease (CLD) was defined as a supplemental oxygen requirement at 36 weeks' gestational age to maintain oxygen saturation >90%. Retinopathy of prematurity (ROP) was defined as stage 2 (with plus disease) or greater than or equal to stage 3.25 Infants were considered to have severe ROP if they received laser treatment to at least 1 eye. Intracranial hemorrhage (ICH) was classified using the 4-level grading system.26 Periventricular leukomalacia was defined as echodensities that progressed to cystic degeneration. All of the infants were examined with serial bedside cranial ultrasounds initiated within the first week of life. These were repeated weekly or biweekly for the first 4 weeks. After 1 month, imaging was repeated before discharge or, more frequently, if there were any abnormal findings. A single neonatologist (Dr Clyman) prospectively evaluated and recorded all of the perinatal/neonatal risk factors and outcome measures during the hospitalization.


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  		TABLE 1 Demographics

 
We also examined several long-term, neurodevelopmental outcomes. Infants surviving to nursery discharge were enrolled in a prospective nursery follow-up clinic for determination of neurodevelopmental outcome as described previously.27,28 Complete age-appropriate developmental examinations were routinely scheduled for the children at 1, 1.5, 2.5, and 4.5 years adjusted age. Age was adjusted for prematurity until 3 years. Our follow-up team traveled to several communities in Northern California to locate infants and perform assessments; infants living in these communities were examined as close to the scheduled ages as possible. Follow-up information was available for 82% of the initial population (n = 446). There were no significant differences between those who were followed and those who were lost to follow-up in gestation (followed: 25.7 ± 0.1; lost: 26.0 ± 0.1 months), male gender (followed: 55%; lost: 51%), antenatal glucocorticoid exposure (followed: 78%; lost: 76%), chorioamnionitis (followed: 22%; lost: 24%), respiratory distress (followed: 83%; lost: 89%), ICH grade 3 or 4 (followed: 4.4%; lost: 8.9%), ICH grade 3 or 4 and/or periventricular leukomalacia (followed: 7%; lost: 11%), respiratory score >3 (followed: 15%; lost: 9%), sepsis (followed: 43%; lost: 37%), NEC (followed: 12%; lost: 6%), CLD (followed: 27%; lost: 26%), ROP (followed: 15%; lost: 8%), indomethacin exposure >3 doses (followed: 33%; lost: 30%), incidence of symptomatic PDA (followed: 28%; lost: 18%), or PDA ligation (followed: 22%; lost: 17%).

A single neonatologist (Dr Piecuch), with training in developmental pediatrics, performed a neurologic examination to determine motor outcome. Final neurologic diagnosis was that obtained at the last assessment. Audiologic status was assessed by behavioral testing, and suspicious examinations were evaluated by brainstem-evoked responses or pure tone audiometry. Visual status was assessed using the near point test or Snellen eye chart. Children with questionable visual status were referred to an ophthalmologist. A single developmental psychologist (Dr Leonard) measured cognitive outcome using the Mental Development Index (MDI) of the Bayley Scales of Infant Development for children <36 months and the full-scale IQ (FSIQ) scores of the Wechsler Preschool and Primary Scale of Intelligence for the 4.5-year evaluation. Abnormal neurologic, neurosensory, and cognitive outcomes were defined as follows. Neurologic included moderate/severe cerebral palsy (hypotonic, spastic diplegia, hemiplegia, or quadriplegia) with functional deficits that required rehabilitative services. Neurosensory included bilateral hearing loss (requiring amplification) and blindness in either eye. Cognitive included MDI or FSIQ scores <70 (2 SDs below the mean of 100). We calculated cognitive outcome using data from the last assessment given to each child (mean age: 45 ± 23 months). We also used the Bayley MDI scores that were obtained between ages 15 and 30 months to look at the population at a narrower point in development.

Statistical Models
We examined the relationship among the incidence of NEC, CLD, ROP, death, and neurodevelopmental impairment with the following aspects of PDA-oriented care: (1) the presence of a symptomatic PDA, (2) the number of indomethacin doses used, (3) the ductus response to prophylactic indomethacin, and (4) the use of surgical ligation. We could not examine the effects of prophylactic indomethacin use on neonatal morbidities, because all of the infants were treated with prophylactic indomethacin. Similarly, we could not examine the effects of prolonged exposure to a symptomatic PDA on neonatal morbidities, because all of the symptomatic PDAs were closed (either pharmacologically and/or surgically) within 5 days of presentation.

We first identified the non–PDA-oriented perinatal and neonatal risk factors that were most significantly associated with the development of ROP, NEC, CLD, death, cerebral palsy, and MDI/FSIQ <70 in our population (Table 2). Estimated odds ratios (ORs) and their 95% confidence intervals were obtained for each risk factor, and a model was built for each morbidity through backward selection using P < .2 as a cutoff to keep variables in the model. We tested for interactions. These perinatal and neonatal risk factors were used in the adjusted model that evaluated the effects of PDA-oriented variables on neonatal morbidity (see model 3 below).


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  		TABLE 2 Neonatal Morbidity Models: Adjusted for All of the Perinatal/Neonatal Variables Present in Table 1

 
We next examined the effects of the different aspects of PDA-oriented care on the development of NEC, CLD, ROP, death, and neurodevelopmental impairment. Our intent was to determine whether a particular PDA-oriented variable had an independent effect on neonatal morbidity or if its effect could be explained by immaturity, by other perinatal/neonatal risk factors, or by ≥1 of the other PDA-oriented variables. Therefore, the PDA-oriented variables were entered into 4 separate logistic regression models (model 1: each individual PDA-oriented variable by itself [the unadjusted, univariate model]; model 2: each individual PDA-oriented variable plus gestational age [a measure of immaturity]; model 3: each individual PDA-oriented variable plus the set of perinatal and neonatal risk factors identified in Table 2; and model 4: each individual PDA-oriented variable, plus gestational age, plus 1 other PDA-oriented variable).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tables 3 to 5 examine the effects of the different aspects of PDA-oriented care on the development of NEC, CLD, ROP, death, and neurodevelopmental impairment. In the initial unadjusted, univariate analysis (model 1), each of the different aspects of PDA-oriented care (number of indomethacin doses used, ductus response to prophylactic indomethacin, presence of a symptomatic PDA, and use of surgical ligation) was either significantly (P < .05) or closely (P < .10) related to the development of NEC, ROP, and death (Table 3). However, once the analyses were adjusted for gestational age (model 2), there was no longer a significant association between the different aspects of PDA-oriented care and ROP, laser-treated ROP (data not shown), NEC, or death (Table 3). Therefore, the elevated risks of ROP, NEC, and death in the univariate models (model 1) could be accounted for by immature gestational age.


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  		TABLE 3 Association Between Neonatal Morbidity During Initial Hospitalization and PDA-Related Variables (Indomethacin Exposure, Symptomatic PDA, and Ligation): Unadjusted, Adjusted for Gestation, and Adjusted for Perinatal/Neonatal Variables

 

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  		TABLE 4 Association Between Long-Term Morbidity and PDA-Related Variables (Indomethacin Exposure, Symptomatic PDA, and Ligation): Unadjusted, Adjusted for Gestation, and Adjusted for Perinatal/Neonatal Variables

 

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  		TABLE 5 Association Between CLD and PDA-Related Variables: Unadjusted, Adjusted for Gestation, Adjusted for Perinatal/Neonatal Variables, and Adjusted for Gestation and Ligation

 
Similarly, in the unadjusted analysis, several aspects of PDA-oriented care were closely related to the combined long-term outcome of neurodevelopmental impairment or death (Table 4, model 1). However, once the analyses were adjusted for gestational age (model 2) or for other perinatal and neonatal risk factors (model 3), there were no longer any significant associations (Table 4). None of the other measures of long-term outcome (cerebral palsy, cognitive delay on last assessment, or cognitive delay at 15–30 months) were significantly associated with any of the PDA-oriented care variables (Table 4).

In the unadjusted model, CLD was also significantly related to the different aspects of PDA-oriented care (Table 5, model 1). However, once the analyses were adjusted for gestational age (model 2) or for other perinatal and neonatal risk factors (model 3), there were no longer any significant associations except for the use of surgical ligation (Table 5). We examined CLD as a function of the combined effects of gestational age, ligation, and each of the remaining PDA-oriented variables (see Table 5, model 4). The adverse association between each of the PDA-oriented variables and CLD completely disappeared when both gestational age and surgical ligation were introduced into the models. With both gestational age and ligation in the model, the OR for the number of indomethacin doses used was only 1.02; the OR for ductus response to prophylactic indomethacin was 1.09; and the OR for the presence of a symptomatic PDA was 0.45 (Table 5, model 4). In contrast, the significant relationship between surgical ligation and CLD in the unadjusted model (model 1: OR: 2.14) was minimally affected by the introduction of either gestational age alone (model 2: OR: 1.97) or by the introduction of gestational age plus each of the other PDA-oriented variables (model 4: relationship between surgical ligation and CLD with both gestation and prophylactic indomethacin doses >3 in the model: OR: 1.79; with both gestation and total number of indomethacin doses >3: OR: 1.94; with both gestation and ductus response to prophylactic indomethacin: OR: 1.87; and with both gestation and presence of a symptomatic PDA: OR: 4.20). The independent relationship between surgical ligation and CLD was unaffected even when all of the significant perinatal and neonatal risk factors were added into the model (model 3: OR: 1.91; Table 5).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study was designed to compare several aspects of PDA-oriented care (the presence of a symptomatic PDA, the number of indomethacin doses used, the ductus response to prophylactic indomethacin, and the use of surgical ligation) with the risk of developing NEC, CLD, ROP, death, or neurodevelopmental impairment. This study was not designed to examine the effects of prophylactic indomethacin use on neonatal morbidities, because, by design, all of the infants were treated with prophylactic indomethacin. Similarly, we could not examine the effects of prolonged exposure (>5 days) to a symptomatic PDA, because all of the symptomatic PDAs were closed, pharmacologically and/or surgically, within 5 days of presentation. Both of these variables have been examined in previous randomized, controlled trials. Indomethacin prophylaxis has been shown, both in individual studies and by meta-analysis, to have no significant impact on the incidence of NEC, CLD, ROP, death, or neurodevelopmental impairment.11,29,30 On the other hand, prolonged exposure to a symptomatic PDA has been shown to increase neonatal morbidity in the small number of controlled trials that have examined this issue.7,8 More recent population analyses have also found an increased incidence in neonatal morbidity after prolonged exposure to a symptomatic PDA.31,32

Because infants were not allowed to have a symptomatic PDA for >5 days, we were able to examine the effects of other PDA-oriented variables without the confounding effects of prolonged exposure to a symptomatic PDA in the analysis. We found that neither the ductus response to prophylactic indomethacin nor a brief (≤5-day) exposure to a symptomatic PDA led to the subsequent development of ROP, NEC, CLD, or death. The apparent morbid effects of these 2 variables, observed in the unadjusted models (model 1), became insignificant when the models were adjusted for gestational age (Tables 3 and 5, model 2). Developmental processes determine the incidence of PDA, its response to indomethacin, and the incidence of ROP, NEC, and CLD.33–37 It is not surprising that morbidities that are similarly caused by interrupted development seem to be associated with each other in univariate analyses.

Similarly, we found that, when gestational age was included in the analysis, the number of indomethacin doses that an infant received (either during the prophylactic treatment course or during the entire hospitalization) was not significantly associated with the incidence of ROP, NEC, or death (Table 3, model 2). The apparent adverse effect of the number of indomethacin doses on the incidence of CLD could be completely explained by the presence of both gestational age and surgical ligation (Table 5, model 4). This is consistent with the results of controlled trials of short versus long courses of indomethacin treatment, where no relationship was found between the duration of indomethacin exposure and the incidence of ROP, NEC, CLD, or death.15

Surgery, during the neonatal period, has been associated with neurodevelopmental problems after preterm birth.38–40 Our findings are somewhat reassuring, because we found no relationship between ductus ligation (or any of the other ductus-oriented factors) and subsequent neurodevelopmental problems (Table 4). On the other hand, surgical ligation was found to be significantly and independently associated with an increased incidence of CLD. The relationship between ligation and CLD was independent of an infant's gestational age (Table 5, model 2) or of other PDA-related variables (model 4). Surgical ligation was still a significant, independent risk factor for CLD, even when other perinatal and neonatal risk factors for CLD were incorporated into the model (Table 5, model 3).

Our study cannot determine whether surgical ligation plays a causative role in the development of CLD or is simply a surrogate marker for infants with a unique developmental profile leading to CLD. Recent findings in premature baboons support the concept that surgical ligation may have a detrimental effect on lung function and growth. Premature newborn baboons, exposed to a moderate-size PDA shunt for 2 weeks, have decreased pulmonary function and arrested alveolar development.41 Pharmacologic closure of the PDA prevented the deterioration in both pulmonary function and alveolar development.41 In contrast, surgical closure of the PDA offered no benefit for either pulmonary function or for alveolar growth or development.42 Similarly, in the only published controlled trial to compare pharmacologic closure of the PDA with surgical ligation,19 infants who were surgically ligated tended to need longer durations of continuous positive airway pressure than those treated with indomethacin (P = .06). In sum, these studies suggest that ductus ligation, while eliminating 1 potential cause for neonatal morbidity, may introduce its own set of problems.

Our findings add to the growing uncertainty about the benefits and risks of surgical ligation1 or of surgery in general during the neonatal period.38–40 Additional investigations will be needed to determine which infants are most likely to benefit from surgical ligation of their PDA and which infants might best be left untreated.


   ACKNOWLEDGMENTS
 
This research was supported by National Institutes of Health grants HL466911 and HL56061 and by a gift from the J. and B. Gates Foundation. This study was carried out in part in the Pediatric Clinical Research Center (Moffitt Hospital, University of California, San Francisco) with funds provided by National Center for Research Resources grant 5 M01 RR-01271, US Public Health Service.

We thank the fellows and attending staff of the Division of Pediatric Cardiology, who have been so helpful in performing and interpreting the echocardiographic studies, and the Intensive Care Nursery and Pediatric Clinical Research Center nurses, without whom this study would not have been possible. Dr Chuck McCulloch provided invaluable statistical advice and support.


   FOOTNOTES
 
Accepted Jan 18, 2007.

Address correspondence to Ronald I. Clyman, MD, University of California, 513 Parnassus Ave, Room 1408 HSW, UCSF Box 0544, San Francisco, CA 94143-0544. E-mail: clymanr{at}peds.ucsf.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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