Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants

Malviya M, Ohlsson A, Shah S

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 14/11/2007
Date of last substantive update: 27/10/2007
Date of last minor update: / /
Date next stage expected 09/11/2009
Protocol first published: Issue 1, 2003
Review first published: Issue 3, 2003

Contact reviewer

Dr Manoj N Malviya
Clinical Fellow, Shared Program in Neonatal-Perinatal Medicine
Division of Neonatology, Department of Paediatrics
University of Toronto
600 University Avenue
Rm 775a
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: 416 586 5128
Facsimile: 416 586 8745
E-mail: malviya2000@yahoo.com

Contribution of reviewers

MM, AO, SS, contributed to all stages of review.
The update of this review was undertaken by AO.

Internal sources of support

Mount Sinai Hospital, Toronto, Ontario, CANADA

External sources of support

None

What's new

This updates the previously published review "Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants" published in The Cochrane Library, Issue 3, 2003 (Malviya 2003).

A repeat search of the literature in July 2007 did not identify any new trials for inclusion.

The conclusions remain the same. However, it should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment. It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 30/07/2007
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis


The way an infant's blood is circulated changes soon after birth. Initially, premature infants have an opening (a patent ductus arteriosus, PDA) between the large blood vessel to the lungs and the large blood vessel that carries oxygenated blood to the rest of the body. Early symptomatic treatment of PDA, when clinical signs first appear, helps reduce the amount of time an infant needs assisted breathing (mechanical ventilation) and the likelihood of chronic lung disease and damaging inflammation of the gut (necrotizing enterocolitis). Standard therapy includes restricting fluids, diuretics, and cyclooxygenase inhibitors like indomethacin or ibuprofen. The PDA is closed surgically if these medical treatments do not work. Only one randomised controlled study could be included in this review (including 154 preterm infants that needed breathing support). Indomethacin and surgery gave similar benefits. There were no differences in deaths during the hospital stay, chronic lung disease, necrotizing enterocolitis, cerebral or other bleeding. Surgery was more effective in closing the PDA (three needed to treat for one to benefit) but it was associated with complications (pneumothorax and retinopathy of prematurity). The one study found was carried out over 20 years ago. Clinical practice has changed a great deal and surgical closure of a PDA is safer. Therefore, whether the results of the study are applicable today is debatable. An update of this review in July 2007 did not identify any additional randomised controlled studies for inclusion, but three observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment .

Abstract



Background


Patent ductus arteriosus (PDA) with significant left to right shunt in preterm infants increases morbidity and mortality. Early closure of the ductus arteriosus may be achieved pharmacologically using cyclooxygenase inhibitors or by surgery. The efficacy of both treatment modalities is well established. However, the preferred initial treatment of a symptomatic PDA in a preterm infant, surgical ligation or treatment with indomethacin, has not been well established.

Objectives


To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (using indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA.

Search strategy


The standard search strategy of the Cochrane Neonatal Review Group was used. This included search of electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - July 2007), CINAHL (1982 - July 2007), EMBASE (1980 - July 2007); and hand search of abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - April 2002) or on line from May 2002 -July 2007. No language restrictions were applied.


Selection criteria


All trials 1) using randomized or quasi-randomized patient allocation, 2) in preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA in the neonatal period (< 28 days) and 3) comparing surgical ligation with medical treatment with cyclooxygenase inhibitors, each used as the initial treatment for closure of PDA.

Data collection & analysis


Assessment of methodological quality and extraction of data for included trials was undertaken independently by the authors. RevMan 4.1 was used for analysis of the data.

Main results


Only one study, trial B in the report of Gersony 1983, was found eligible. No additional studies were identified in the literature searches performed in July 2007. The trial compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the primary treatment. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen, mefenamic acid) were found. Trial B of Gersony 1983 enrolled 154 infants. The study found no statistically significant difference between surgical closure and indomethacin treatment in mortality during hospital stay, chronic lung disease, other bleeding, necrotizing enterocolitis, sepsis, creatinine level, or intraventricular hemorrhage. There was a statistically significant increase in the surgical group in incidence of pneumothorax [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)] and retinopathy of prematurity stage III and IV [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20), NNH 9 (95% CI 5, 50] compared to the indomethacin group. There was as expected a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21), NNT 3 (95% CI 2, 4)].

Reviewers' conclusions


The data regarding net benefit/harm are insufficient to make a conclusion as to whether surgical ligation or medical treatment with indomethacin is preferred as initial treatment for symptomatic PDA in preterm infants. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.

Background


For more than 20 years it has been recognized that a significant left to right shunt through a patent ductus arteriosus (PDA) in preterm infants increases morbidity and mortality (Cotton 1978b; Jacob 1980; Thibeault 1975). The reported incidence of PDA ranges from less than 10% to 60% depending on gestational age, day of life and diagnostic criteria used (Duddell 1984; Ellison 1983). A symptomatic PDA may occur in up to 50% of infants with birth weight less than 1500 grams (Mouzinho 1991). Infants with respiratory distress syndrome (RDS) (Thibeault 1975), perinatal asphyxia (Cotton 1981), and those who have received excessive fluids during the first days of life (Bell 1980) are more susceptible to the development of a clinically symptomatic PDA. A symptomatic PDA increases the ventilation and oxygen requirements, and increases the risk of intraventricular hemorrhage (Duddell 1984) and chronic lung disease (Brown 1979) in very low birth weight (VLBW) infants. The phenomenon of diastolic steal associated with a PDA may cause renal impairment, intestinal ischemia, necrotizing enterocolitis (NEC) and reduced middle cerebral artery blood flow velocity (Martin 1982; Nestrud 1980; Shimada 1994; Weir 1999).

The clinical criteria used for the diagnosis of a symptomatic PDA are the presence of a heart murmur, bounding pulses, tachycardia, hyperdynamic precordial impulse, widened pulse pressure or worsening respiratory status (tachypnea and increasing fraction of inspired oxygen and/or ventilatory requirements) (Davis 1995). Echocardiographic and Doppler criteria for the confirmation of a symptomatic PDA include the following (Dani 2000; De Carolis 2000; Lago 2002):
1. Demonstration of left to right shunt
2. Left atrial:aortic root ratio > 1.3
3. Ductal size greater than 1.5 mm
4. Disturbed diastolic flow in the main pulmonary artery with a diastolic backflow in the aorta immediately below the ductus arteriosus and a forward flow above the ductal insertion

There are numerous reports suggesting that prophylactic closure of the ductus arteriosus reduces the incidence of grade 3 or 4 IVH and need for surgical ligation (Yeh 1981; Fowlie 1996; Fowlie 2002). Also, early symptomatic treatment of PDA (i.e. when clinical signs first appear) has been shown to decrease the incidence of chronic lung disease, duration of mechanical ventilation and necrotizing enterocolitis when compared with late symptomatic treatment (i.e. after signs of congestive cardiac failure) (Clyman 1996). Standard therapy for a PDA includes fluid restriction, diuretics, and cyclooxygenase inhibitors like indomethacin or ibuprofen, with surgical ligation reserved for medical failures. In 1976, it was first demonstrated that closure of the ductus arteriosus could be achieved pharmacologically using the cyclooxygenase inhibitor indomethacin (Heymann 1976; Friedman 1976). About the same time, Cotton et al (Cotton 1978b) showed the beneficial effect of surgical intervention to close the ductus arteriosus in preterm infants with a significant left to right shunt.

Efficacy and toxicity of indomethacin and other cyclooxygenase inhibitor drugs have been explored extensively and many variations in dosage regimens have been reported in the literature (Yanowitz 1998; Ng 1997; Patel 2000; Van Overmeire 2000). Rennie and Cooke (Rennie 1991) found higher ductal closure rates and fewer renal side effects with low dose prolonged indomethacin therapy (0.1 mg per kilogram given daily for six days) compared with the conventional three dose regimen (0.2 mg per kilogram given at 12-hour intervals). A study comparing the efficacy and toxicity of ibuprofen vs. indomethacin found similar ductal closure rates in both treatment groups except that indomethacin was more likely to be associated with oliguria (Van Overmeire 2000). There is a risk of failure to close the PDA with cyclooxygenase inhibitors. Failure of ductal closure with indomethacin is reported in between 30% to 40% of treated infants (Gersony 1983; Palder 1987). This may be more likely in the very immature infant (Trus 1993; Palder 1987; Perez 1998; Weiss 1995). Narayanan et al (Narayanan 2000) reported that 41% of infants treated with indomethacin for symptomatic PDA and 21% of infants given prophylactic indomethacin required eventual ductal ligation. Indomethacin treatment has been associated with several adverse effects such as transient or permanent alterations in renal function (Gersony 1983; Betkerur 1981; Van Bel 1991), necrotizing enterocolitis, gastrointestinal perforation (Grosfeld 1996) and impairment of cerebral blood flow velocity (Edwards 1990; Ohlsson 1993). Indomethacin prophylaxis has been shown to reduce the incidence of PDA; however, it does not significantly affect the rate of survival without neurosensory impairment at 18 months (Schmidt 2001).

Surgical ligation in preterm neonates with a symptomatic PDA has been shown to be successful with minimal complications (Palder 1987; Pokharel 1998; Satur 1991; Chen 1999). There are reports suggesting that surgical ligation may be the preferred first line of treatment compared to indomethacin in preterm infants less than 800 g (Palder 1987; Trus 1993). One study has shown that PDA is less likely to close with indomethacin if PDA is associated with large LA/AO (left atrial-aortic) ratio on echocardiography and surgical ligation may be the better option (Trus 1993). The reported success rates for surgical closure of PDA are 98% to 100% (Koehne 2001; Palder 1987). However, occasional failure of surgery to close a symptomatic PDA can occur; for example, if the ductal clip is malpositioned or dislodged (Koehne 2001). Some investigators have reported significant complications associated with surgical ligation including tension pneumothorax, hypothermia, intra operative bleeding, phrenic nerve palsy, wound infection, vocal cord palsy and thoracic scoliosis (Mikhail 1982; Koehne 2001; Seghaye 1997; Zbar 1996). In a retrospective study comparing indomethacin with surgical ligation, the overall fatality rates were found to be 16 of 101 (16%) for indomethacin and 14 of 55 (25%) for surgery (Koehne 2001). Although open surgical division is a safe and reliable procedure, concerns about chest wall deformity (Westfelt 1991) and postoperative pain syndromes associated with standard posterolateral thoracotomy have motivated a search for a less traumatic approach. Video assisted thoracoscopic surgery (VATS), a recent advancement in surgical management of PDA, uses endoscopic instruments through 3 mm incisions in the chest wall to approach the PDA (Burke 1999).

Although both surgical and pharmacological interventions for ductal closure are widely used, morbidity and mortality associated with these therapies have not been systematically reviewed. Even though there may be a general consensus to use indomethacin as the initial therapy for a symptomatic PDA, and to reserve surgical ligation for indomethacin failures, this therapeutic approach may not represent the optimal management for PDA in the extremely preterm neonate.

This review compares the effectiveness and safety of surgical versus medical treatment with cyclooxygenase inhibitor drugs as initial treatment in preterm infants with a symptomatic PDA.

Objectives


Primary objective

1. To compare the effect of surgical ligation of PDA vs. medical treatment with cyclooxygenase inhibitors (indomethacin, ibuprofen, or mefenamic acid), each used as the initial treatment, on neonatal mortality in preterm infants with a symptomatic PDA.

Secondary objectives

To determine in subgroup analyses the effectiveness and safety of surgical ligation vs. medical treatment with cyclooxygenase inhibitors to close the symptomatic PDA in relation to the following criteria:


Criteria for considering studies for this review



Types of studies


Randomized or quasi-randomized controlled trials.

Types of participants


Preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 grams) with symptomatic PDA diagnosed either clinically or by ECHO criteria in the neonatal period (< 28 days).

Types of interventions


Surgical ligation for closure of PDA vs. medical treatment with cyclooxygenase inhibitors, each used as the initial treatment. Surgical ligation after failure of medical treatment with cyclooxygenase inhibitors was incorporated in the medical arm. The cyclooxygenase inhibitors may have been used in any dose and any number of repeated courses.

Types of outcome measures


Studies that reported one or more of the following outcomes:

Primary outcome
All causes of mortality during the initial hospital stay

Secondary outcomes


Search strategy for identification of studies


See: Cochrane Neonatal Review Group search strategy.

The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007) and MEDLINE (1966 - July 2007) were searched using MeSH terms: newborn, infant, premature (or preterm) or low birth weight infant, patent ductus arteriosus or PDA, ligation, and cyclooxygenase inhibitors; indomethacin, ibuprofen, mefenamic acid.

Other data bases that were searched included: EMBASE (1980 - July 2007); CINAHL (1982 - July 2007); and the reference list of identified trials and abstracts of Pediatric Academic Societies annual meetings published in Pediatric Research (1990 - July 2002) or electronically (May 2002 - July 2007). References lists of published narrative and systematic reviews were reviewed. Unpublished data were not sought. No language restrictions were applied. The candidate articles were screened by three review authors (MM, AO, SS) to identify articles eligible for inclusion in the review. For the update of this review, AO undertook the literature search.

Methods of the review


All abstracts and published full reports identified as potentially relevant by the literature search were assessed for inclusion in the review by the three review authors. The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of studies. Independent quality assessments were conducted by the three authors, who were not blinded to authors, institution or journal of publication, using the following criteria:
Blinding of randomization?
Blinding of outcome measure assessment?
Completeness of follow up?
There are three potential answers to these questions - yes, can't tell, no

Each author extracted data separately using pre-designed data abstraction forms, then compared and resolved differences. One reviewer (MM) entered data into RevMan and the others cross-checked the printout against their own data. Disagreements were resolved by consensus.

The statistical analyses followed the recommendations of the Cochrane Neonatal Review Group. The treatment effect estimators were relative risk (RR), risk difference (RD), number needed to treat (NNT) or number needed to harm (NNH) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. All estimates of treatment effects were reported with 95% confidence intervals (CI). A fixed effect model was to be used for meta-analyses. Subgroup analyses were performed according to the criteria listed under objectives. Sensitivity analyses were performed.

Description of studies


Three studies assessing the effect of surgical ligation versus medical treatment as a primary treatment for closure of symptomatic PDA in preterm infants were identified (Levitsky 1976; Cotton 1978b; Gersony 1983). All these studies were published as full text articles. However, the studies by Levitsky et al and Cotton et al were excluded because cyclooxygenase inhibitors were not a part of the medical treatment protocol, which consisted only of fluid restriction and digoxin. The study performed by Gersony 1983 includes a report of two trials, trial A and trial B; trial B was eligible for inclusion in this review. The updated literature search in July 2007 did not identify any additional studies for inclusion.

Gersony 1983 - In this study, 421 preterm infants weighing < 1750 grams with symptomatic PDA were entered to evaluate the role of indomethacin. Randomization was done at two stages. In stage one (trial A), infants with symptomatic PDA were randomized to either indomethacin or placebo. In addition, both the groups received usual medical management (fluid restriction, diuretics, and/or digoxin). In stage two (trial B) infants in the placebo arm of trial A whose PDA remained symptomatic (increased pulse pressure and positive findings on echocardiogram or chest radiograph) and who required significant respiratory support (assisted ventilation for seven or more consecutive days, deteriorating respiratory status or inability to decrease level of respiratory support over a 72-hour period despite maximum medical therapy) were randomized to either surgical closure of PDA or indomethacin treatment. Clinical and echocardiographic criteria were used to diagnose PDA for study entry and to assess the response of treatment groups. Outcome variables measured included ductal closure rate, mortality before hospital discharge, incidences of adverse conditions during hospitalization, length of hospital stay, and duration of respiratory support. Outcomes for all 421 infants were reported. Trial B included 154 infants (79 randomized to surgical group, and 75 to indomethacin group). Trial B of this larger study is relevant to this review and hence outcomes of trial B are reviewed.

Methodological quality of included studies


Gersony 1983 - This was multicenter randomized trial performed at 13 clinical centers in USA. The assignments in trial A were done by random number generation, within blocks of nine (three indomethacin, six placebo). In trial B assignments were done by random number generation at the coordinating center using sealed envelopes. Physicians were not blinded to the intervention, as surgery was one of the treatments. Follow-up was complete. Intention to treat analysis was performed. Blinding of outcome measurements in trial B is not mentioned in the report.

Results


SURGICAL LIGATION VS. MEDICAL TREATMENT WITH INDOMETHACIN (COMPARISON 01):

The results of this review are based on trial B by Gersony 1983. All comparisons are between surgery and medical (indomethacin) treatments. No trials comparing surgery to other cyclooxygenase inhibitors (ibuprofen or mefenamic acid) were found.

Mortality during hospital stay (Outcome 01.01):
There was no statistically significant difference between the two groups: [RR 0.67 (95% CI 0.34, 1.31); RD -0.07 (95% CI -0.20, 0.05)].

Failure of ductal closure (Outcome 01.02):
One infant in the surgical group died before surgery. No operated infant in the surgical group had failed ductal closure. In 33% of the infants in indomethacin group the ductus failed to close and these infants required back up surgery. There was a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group: [RR 0.04 (95% CI 0.01, 0.27); RD -0.32 (95% CI -0.43, -0.21); NNT 3 (95% CI 2, 4)].

CLD (Outcome 01.03):
There was no statistically significant difference between the two groups: [RR 1.28 (95% CI 0.83, 1.98); RD 0.09 (95% CI -0.06, 0.24)].

Intraventricular hemorrhage (Outcome 01.04):
There was no statistically significant difference between the two groups: [RR 0.83 (95% CI 0.32, 2.18); RD -0.02 (95% CI -0.11, 0.08)].

NEC (Outcome 01.05):
There was no statistically significant difference between the two groups: [RR 0.95 (95% CI 0.29, 3.15); RD 0.00 (95% CI -0.08, 0.07)].

Creatinine level > or = 1.8 mg/dl (Outcome 01.06):
There was no statistically significant difference between the two groups: [RR 0.57 (95% CI 0.14, 2.30); RD -0.03 (95% CI -0.10, 0.04)].

ROP stage III and IV (Outcome 01.07):
There was a statistically significant increase in the surgical group compared to the indomethacin group: [RR 3.80 (95% CI 1.12, 12.93); RD 0.11 (95% CI 0.02, 0.20); NNH 9 (95% CI 5, 50].

Pneumothorax (Outcome 01.08):
There was a statistically significant increase in the incidence of pneumothorax in the surgical group: [RR 2.68 (95% CI 1.45, 4.93); RD 0.25 (95% CI 0.11, 0.38); NNH 4 (95% CI 3, 9)].

Sepsis (Outcome 01.09):
There was no statistically significant difference between the two groups: [RR 1.14 (95% CI 0.62, 2.09); RD 0.03 (95% CI -0.10, 0.16)].

Other bleeding (pulmonary, gastrointestinal tract and disseminated intravascular coagulation) (Outcome 01.10):
There was no statistically significant difference between the two groups: [RR 1.54 (95% CI 0.68,3.51); RD 0.06 (95% CI -0.05, 0.17)].

Trial B of Gersony 1983 found no significant difference in trial B for duration of mechanical ventilation (more than 14 days) or duration of hospital stay (mean days of hospital stay in surgical group was 94 days and in indomethacin group was 83 days).

Trial B of Gersony 1983 did not make any comments on the following outcome variables:
PVL, thrombocytopenia, gastrointestinal perforation, time to reach full enteral feeds and long-term neurodevelopmental outcome.

The preplanned subgroup analyses could not be performed due to inability to get the necessary data from the report.

Discussion


Only one study, trial B in Gersony 1983, was eligible for inclusion in this review. An updated search of the literature in July 2007 did not identify any additional studies. The trial of Gersony 1983 compared the effect of surgical ligation of PDA vs. medical treatment with indomethacin, each used as the initial treatment after failure of placebo and usual medical management in preterm infants with a symptomatic PDA. This trial found no statistically significant difference in mortality at discharge between the two groups.

Trial B of Gersony 1983 found a statistically significant decrease in failure of ductal closure rate in the surgical group as compared to the indomethacin group (1% vs 30%). However, it is important to note here that PDA's that closed spontaneously in Trial A (35% in the placebo group) would have been attributed to indomethacin if indomethacin had been the primary treatment. Thus, the difference in closure rates between the surgery and indomethacin groups observed in Trial B likely underestimates the difference that would have been observed if trial entry had occurred earlier.

Trial B of Gersony 1983 found significantly higher incidences of pneumothorax and ROP of stage III and IV in the surgical ligation group compared to the indomethacin group. The incidence of pneumothorax reported in the study by Gersony et al is higher in both groups as compared to incidences reported in other retrospective and prospective studies. The incidence of pneumothorax reported with surgical closure in other studies varies between 6 to 10% (Cotton 1978b; Satur 1991; Koehne 2001; Palder 1987). The higher incidences of pneumothorax found in the study by Gersony et al may be due to delayed intervention or due to the surgery itself. The surgical technique of PDA ligation is at the discretion of the surgeon and some surgeons perform extrapleural dissection in an effort to avoid need for intercostal drain postoperatively (Palder 1987). Others use a transpleural approach, with care to avoid disrupting the visceral pleura and thus avoid need for intercostal drain (Miles 1995). Some surgeons use an intrapleural approach to the PDA and routinely insert a chest drain postoperatively (Niinikoski 2001). Gersony et al (Gersony 1983) did not describe the surgical technique in the report making it difficult to comment on the etiology of pneumothorax.

Trial B of Gersony 1983 found significantly higher incidence of ROP of stage III and IV in the surgical ligation group compared to the indomethacin group. The incidence of ROP reported with surgical closure varies between 1 to 10% in other studies (Cotton 1978b; Satur 1991; Koehne 2001). This particular finding had not been noted by other clinicians using indomethacin or surgical closure. No biologically plausible explanation for this association in the study by Gersony et al is apparent.

Recently, three studies addressed the possible association between surgical closure of a PDA and neurosensory impairments and/or CLD (Kabra 2007; Raval 2007; Chorne 2007). Kabra et al (Kabra 2007) studied 426 infants with a symptomatic PDA, 110 of whom underwent PDA ligation and 316 of whom received medical therapy only. All infants were enrolled in the multicenter trial of Indomethacin Prophylaxis in Preterms (TIPP) and were observed to a corrected age of 18 months. The adjusted odds ratio comparing those who survived after PDA ligation (n = 95) compared to those who survived after receiving medical therapy only (n = 245) for neurosensory impairment was 1.98 (95% CI 1.18, 3.30), for CLD was 1.81 (95% CI 1.19, 3.03) and for severe ROP was 2.20 (95% CI 1.19, 4.07). Raval et al (Raval 2007) conducted a retrospective review of 197 infants less than 38 weeks of postmenstrual age, undergoing PDA ligation via thoracotomy between January 1, 1992, and January 1, 2004. Only 44 (22%) survived to discharged without CLD (defined as need for supplemental oxygen at 36 weeks postmenstrual age. In a retrospective cohort study Chorne et al (Chorne 2007) included all infants (< 28 weeks gestation) admitted to the William H. Tooley Nursery at University of California San Francisco and who were treated according to a PDA care-oriented protocol, which included prophylactic indomethacin. Logistic regression analysis was used to examine the effects of several PDA-related variables (presence of symptomatic PDA, the number of indomethacin doses used, the ductus response to indomethacin, and the use of surgical ligation) on the incidence of ROP , NEC, CLD, death, and neurodevelopmental impairment. Most of the predictive effects that the presence of a PDA and its treatment had on neonatal morbidity could be accounted for by the infants' immature gestation. Use of surgical ligation was significantly associated with the development of CLD (adjusted OR 1.91, 95% CI 1.02, 3.57) and was independent of immature gestation, other PDA-related variables, or other perinatal and neonatal risk factors known to be associated with CLD. The corresponding adjusted OR for ROP was 1.00 (95%CI 0.45, 2.21), for neurodevelopmental impairment or death was 1.18 (95% CI 0.56, 2.49) and for NEC was 1.19 (95% CI 0.61, 2.33). Although the study design was not a randomized controlled trial comparing surgical to medical closure of a PDA, the findings in these three studies suggest an increased risk of one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment . It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes as could peri-operative care.

Trial B of Gersony 1983 found no statistically significant difference in other morbidity variables (CLD, NEC, other bleeding, sepsis, creatinine clearance, duration of hospital stay, IVH or duration of mechanical ventilation).The duration of mechanical ventilation and hospital stay were measured from admission to NICU, and not from the day of randomization in Trial B. The two could be quite different if randomization in trial B was rather late.

Trial B of Gersony 1983 has the following limitations as far as objectives of this review are concerned

The review authors were surprised at the paucity of trials comparing surgical vs. medical treatment with cyclooxygenase inhibitors for symptomatic PDA in preterm infants. There are several possible reasons for this.


Reviewers' conclusions



Implications for practice


The results of this review, which include data from only one clinical trial, do not allow development of clear guidelines for the initial treatment of symptomatic PDA in preterm infants. The data are insufficient regarding net benefit/harm to make a conclusion as to whether surgical ligation or medical treatment with cyclooxygenase inhibitors is preferable as initial treatment for symptomatic PDA in preterm infants. There are concerns about an increased risk of ROP and CLD following PDA ligation based on the study included in this review. It should be noted that three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment. It is possible that the duration of the "waiting-time" and transport to another facility with surgical capacity to have the PDA ligated could adversely affect outcomes, as could the perioperative care.

Implications for research


Future research should be directed toward addressing the question of whether surgical ligation is preferred to indomethacin for closure of a symptomatic PDA in preterm infants. The rationale for the study question includes:
1. Lack of randomized controlled trials in this field
2. Some retrospective studies suggesting better outcomes in extremely-low-birth-weight infants with surgical ligation compared to indomethacin therapy. However, three recent observational studies indicated an increased risk for one or more of the following outcomes associated with PDA ligation; chronic lung disease, retinopathy of prematurity and neurosensory impairment.
3. Morbidity (NEC, gastrointestinal perforation and renal side effects) and failure of ductus to close are still concerns associated with indomethacin treatment
4. Closure of PDA remains unpredictable after indomethacin treatment as compared to the definitive effect of surgical ligation.

The important subgroups will be extremely-low-birth-weight infants and infants with large PDA with left atrial to aortic ratio of more than 1.5 on echocardiography, because of high failure rate of ductal closure associated with indomethacin treatment in these infants. The study should evaluate short-term outcomes such as death and pulmonary morbidity as well as clinically significant long-term outcomes such as neurodevelopmental status and CLD.

Acknowledgements



Potential conflict of interest


None

Characteristics of included studies

StudyMethodsParticipantsInterventionsOutcomesNotesAllocation concealment
Gersony 198313 centre, randomized controlled trial
I. Blinding of randomization -Yes
II. Blinding of intervention,
trial B - No
III Blinding of outcome measurement (s)
trial B - Not mentioned in the report
IV Complete follow-up - Yes		Inclusion criteria:
1. Infants with birth weight < or = to 1750 gm with hemodynamically significant PDA
Exclusion criteria
1. Birth weight < or = to 500 gm
2. Congenital anomalies
3. Chromosomal abnormalities
4. Death within the first 24 hours
5. Age more than 14 days on admission to study centre
6. Lack of parental consent for monitoring
7. BUN more than 30mg/dl
8. Serum creatinine more than 1.8 mg/dl
9. Total urine output less than 0.6 ml/kg/hr
10. Platelet count < 60,000/mm
11. Stool Hematest > or = to 3+ ( or moderate to large)
12. Evidence of bleeding diathesis
13. Clinical or noninvasive evidence of intracranial hemorrhage within preceding seven days
Demographic data: Values presented as number or percentage
Total number of infants entered in trial B =154
Surgery = 79
Indomethacin = 75		79 infants underwent surgical closure for PDA.
75 infants received intravenous indomethacin at 12-hour intervals for a total of three doses, unless contraindications developed or there was evidence of complete ductal closure. Infants received 0.2 mg/kg of body weight as initial dose and then a second and third dose depending upon infant age at time of entry, 0.1 mg/kg or 0.2 mg/kg or 0.25 mg/kg if less than 2 days or 2- 7 days or more than 8 days respectively.
Ductal closure rates, hospital mortality, duration of respiratory support, length of hospital stay. Incidence of adverse events (CLD, pneumothorax, IVH, NEC, sepsis, other bleeding, creatinine clearance > or = to 1.8, ROP of grade III and IV)
A diagnosis of significant PDA was made by clinical criteria (heart rate > 170 bpm, increased pulse pressure, hyperactive precordium, hepatomegaly > 3cms) and echocardiographic demonstration of left atrial to aortic root ratio of = or > 1.15
National collaborative study involving 13 centres in USA
Study period: April 1979 to April 1981.

Details about surgical procedure were not mentioned.

Postnatal age at which babies were randomized to surgical ligation or indomethacin was not clear

A
BUN = Blood urea nitrogen
PDA = Patent ductus arteriosus

Characteristics of excluded studies

StudyReason for exclusion
Cotton 1978aThe study compared medical management versus surgical closure as primary treatment for symptomatic PDA in preterm infants, however the study did not use cyclooxygenase inhibitors in the medical management protocol.
Levitsky 1976The study compared medical management versus surgical closure as primary treatment for symptomatic PDA in preterm infants, however the study did not use cyclooxygenase inhibitors in the medical management protocol.

References to studies

References to included studies

Gersony 1983 {published data only}

Gersony WM, Peckham GJ, Ellison RC, Miettenen OS, Nadas AS. Effect of indomethacin in premature infants with patent ductus arteriosus: Results of a national collaborative study. Journal of Pediatrics 1983;102:895-906.

References to excluded studies

Cotton 1978a {published data only}

Cotton RB, Stahlman MT, Bender HW, Graham TP, Catterton WZ, Kovar I. Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. Journal of Pediatrics 1978;93:647-51.

Levitsky 1976 {published data only}

Levitsky S, Fisher E, Vidyasagar D, Hastreiter AR, Bennett E, Raju TN, Roper K. Interruption of patent ductus arteriosus in premature infants with respiratory distress syndrome. Annals of Thoracic Surgery 1976;22:131-7.

* indicates the primary reference for the study

Other references

Additional references

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based on clinical staging. Annals of Surgery 1978;187:1-7.

Bell 1980

Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. New England Journal of Medicine 1980;302:598-604.

Betkerur 1981

Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS. Indomethacin and its effect on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus. Pediatrics 1981;68:99-102.

Brown 1979

Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. Journal of Pediatrics 1979;95:865-6.

Burke 1999

Burke RP, Jacobs JP, Cheng W, Trento A, Fontana GP. Video-assisted thoracoscopic surgery for patent ductus arteriosus in low birth weight neonates and infants. Pediatrics 1999;104:227-30.

Chen 1999

Chen KB, Tu KT, Cheng HC, Wu YL, Chang JS. The anesthetic management of a preterm infant weighing 500 gms undergoing ligation of patent ductus arteriosus. Acta Anaesthesiologica Sinica 1999;37:89-92.

Chorne 2007

Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity. Pediatrics 2007;119:1165-74.

Clyman 1996

Clyman RI. Recommendations for the postnatal use of indomethacin: An analysis of four separate treatment strategies. Journal of Pediatrics 1996;128:601-7.

Cotton 1978b

Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. Journal of Pediatrics 1978;92:467-73.

Cotton 1981

Cotton RB, Lindstrom DP, Stahlman MT. Early prediction of symptomatic patent ductus arteriosus from perinatal risk factors: a discriminant analysis model. Acta Paediatrica Scandinavica 1981;70:723-7.

Dani 2000

Dani C, Bertini G, Reali MF, Murru P, Fabris C, Vangi V, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatrica 2000;89:1369-74.

Davis 1995

Davis P, Turner-Gomes D, Cuningham K, Way C, Roberts R, Schmidt B. Precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus. Archives of Pediatric and Adolescent Medicine 1995;149:1136-41.

De Carolis 2000

De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. European Journal of Pediatrics 2000;159:364-8.

Duddell 1984

Duddell GG, Gersony M. Patent ductus arteriosus in neonates with severe respiratory disease. Journal of Pediatrics 1984;104:915-20.

Edwards 1990

Edwards AD, Wyatt JS, Ricardson C, Potter A, Cope M, Delpy DT. Effects of indomethacin on cerebral hemodynamics in very preterm infants. Lancet 1990;335:1491-5.

Ellison 1983

Ellison RC, Peckham GJ, Lang P, Taner NS, Lerer TJ, Lin L, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71:364-72.

Fowlie 1996

Fowlie PW. Prophylactic Indomethacin. Systematic review and meta analysis. Archives of Disease in Childhood 1996;74:F81-7.

Fowlie 2002

Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 3, 2002.

Friedman 1976

Friedman WF, Hirschklau MJ, Printz MP, Pitlick PT, Kirkpatrick SE. Pharmacological closure of patent ductus arteriosus in the premature infant. New England Journal of Medicine 1976;295:526-9.

Grosfeld 1996

Grosfeld JL, Chaedt M, Molinari F. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Annals of Surgery 1996;224:350-7.

Heymann 1976

Heymann MA, Rudolph AM, Silverman NH. Closure of the patent ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. New England Journal of Medicine 1976;295:530-3.

ICROP 1984

Committee for classification of retinopathy of prematurity. An international classification of retinopathy of prematurity. Archives of Ophthalmology 1984;102:1130-4.

Jacob 1980

Jacob J, Gluck L, DiSessa T, Edwards D, Kulovich M, Kurlinski J, et al. The contribution of the patent ductus arteriosus in the neonate with severe respiratory distress syndrome. Journal of Pediatrics 1980;96:79-87.

Kabra 2007

Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A, and the Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms. Journal of Pediatrics 2007;150:229-34.

Koehne 2001

Koehne PS, Bein G, Alexi-Meskhishvili V, Weng Y, Buhrer C, Obladen M. Patent ductus arteriosus in very low birthweight infants: complication of pharmacological and surgical treatment. Journal of Perinatal Medicine 2001;29:327-34.

Lago 2002

Lago P, Bettiol T, Salvadari S, Pitassi I, Vianello A, Chiandetti L, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. European Journal of Pediatrics 2002;161:202-7.

Martin 1982

Martin CG, Snider AR, Katz SM, Peabody JL, Brady JP. Abnormal cerebral flow patterns in preterm infants with a large patent ductus arteriosus. Journal of Pediatrics 1982;101:587-93.

Mikhail 1982

Mikhail M, Lee W, Toews W, Synhorst DP, Hawes CR, Hernandez J, et al. Surgical and medical experience with 734 premature infants with patent ductus arteriosus. Journal of Thoracic and Cardiovascular Surgery 1982;83:349-57.

Miles 1995

Miles RH, DeLeon SY, Muraskas J, Myers T, Quinones JA, Vitullo DA, et al. Safety of patent ductus arteriosus closure in premature infants without tube thoracostomy. Annals of Thoracid Surgery 1995;59:668-70.

Mouzinho 1991

Mouzinho AI, Rosenfeld CR, Risser R. Symptomatic patent ductus arteriosus in very low birth weight infants. Early Human Development 1991;27:65-77.

Narayanan 2000

Narayanan M, Cooper B, Weiss H, Clayman RI. Prophylactic indomethacin: factors determining permanent ductus arteriosus closure. Journal of Pediatrics 2000;136:330-7.

Nestrud 1980

Nestrud RM, Hill DE, Arrington RW, Beard AG, Dungan WT, Lau PY, et al. Indomethacin treatment in patent ductus arteriosus. A double blind study utilising indomethacin plasma levels. Developmental Pharmacology and Therpauetics 1980;1:125-36.

Ng 1997

Ng PC, So KW, Fok TF, Yam MC, Wong MY, Wong W. Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants. Journal of Paediatrics and Child Health 1997;33:324-28.

Niinikoski 2001

Niinikoski H, Alanen M, Parvinen T, Aantaa R, Ekblad H, Kero P. Surgical closure of patent ductus arteriosus in very-low-birth-weight infants. Pediatric Surgery International 2001;17:338-41.

Ohlsson 1993

Ohlsson A, Bottu J, Gowan J, Ryan ML, Fong K, Myhr T. Effect of indomethacin on cerebral blood flow velocities in very low birth neonates with patent ductus arteriosus. Developmental Pharmacology and Therapeutics 1993;20:100-6.

Palder 1987

Palder SB, Schwartz M, Tyson K, Marr C. Management of patent ductus arteriosus: comparison of operative vs pharmacologic treatment. Pediatric Surgery 1987;22:1171-4.

Papile 1978

Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1500 grams. Journal of Pediatrics 1978;92:529-34.

Patel 2000

Patel J, Roberts I, Azzopardi D, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47:36-41.

Perez 1998

Perez CA, Bustroff Silva JM, Villasenor E, Fonkalsrud EW, Atkinson JB. Surgical ligation of patent ductus arteriosus in very low birth weight infants: is it safe? American Surgeon 1998;64:1007-9.

Pokharel 1998

Pokharel R, Hisano K, Yasufuku M, Ataka K, Okada M, Yoshimoto S. Ligation of medically refracted patent ductus arteriosus (PDA) in an extremely low body weight premature infant. Surgery Today 1998;28:1290-4.

Raval 2007

Raval MV, Laughon MM, Bose CL, Phillips JD. Patent ductus arteriosus ligation in premature infants: who really benefits, and at what cost? Journal of Pediatric Surgery 2007;42:69-75.

Rennie 1991

Rennie JM, Cooke RW. Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Archives of Disease in Childhood 1991;66:55-8.

Satur 1991

Satur CR, Walker DR, Dickinson DF. Day case ligation of patent ductus arteriosus in preterm infants. A ten year review. Archives of Disease in Childhood 1991;66:477-80.

Schmidt 2001

Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. New England Journal of Medicine 2001;344:1966-72.

Seghaye 1997

Seghaye MC, Grabitz R, Alzen G, Trommer F, Horchen H, Messmer BJ, et al. Thoracic sequelae after surgical closure of the patent ductus arteriosus in premature infants. Acta Paediatrics 1997;86:213-6.

Shimada 1994

Shimada S, Kasai T, Konishi M, Fujiwara T. Effects of patent ductus arteriosus on left ventricular output and oxygen blood flow in preterm infants with respiratory distress syndrome treated with surfactant. Journal of Pediatrics 1994;125:270-7.

Thibeault 1975

Thibeault DW, Emmanouilides GC, Nelson RJ, Lachman RS, Rosengart RM, Oh W. Patent ductus arteriosus complicating the respiratory distress syndrome in preterm infants. Journal of Pediatrics 1975;86:120-6.

Trus 1993

Trus T, Winthrop AL, Pipe S, Shah J, Langer JC, Lau G. Optimum management of patent ductus arteriosus in neonate weighing less than 800 g. Journal of Pediatric Surgery 1993;28:1137-9.

Van Bel 1991

Van Bel F, Guit GL, Schipper J, Van de Bor M, Baan J. Indomethacin induced changes in renal blood flow velocity waveform in premature infants investigated with color doppler imaging. Journal of Pediatrics 1991;118:621-6.

Van Overmeire 2000

Van Overmeire B, Smets K, Lecoutere D, Van De Broek H, Weyler J, De Groote K, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New England Journal of Medicine 2000;343:674-81.

Weir 1999

Weir FJ, Ohlsson A, Myhr TL, Fong K, Rayan ML. A patent ductus arteriosus is associated with reduced middle cerebral artery blood flow velocity. European Journal of Pediatrics 1999;158:484-7.

Weiss 1995

Weiss H, Cooper B, Brook M, Schlueter M, Clayman RI. Factors determining reopening of the ductus arteriosus after successful clinical closure with indomethacin. Journal of Pediatrics 1995;127:466-9.

Westfelt 1991

Westfelt JN, Nordwall A. Thoracotomy and scoliosis. Spine 1991;16:1124-25.

Yanowitz 1998

Yanowitz TD, Yao AC, Werner JC, Pettigrew KD, Oh W, Stonestreet BS. Effects of prophylactic low dose indomethacin on hemodynamics in very low birth weight infants. Journal of Pediatrics 1998;132:28-34.

Yeh 1981

Yeh TF, Luken JA, Thalji A, Raval D, Carr I, Pildes RS. Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus - a double-blind controlled study. Journal of Pediatrics 1981;98:137-45.

Zbar 1996

Zbar RI, Chen AH, Behrendt DM, Bell EF, Smith RJ. Incidence of vocal cord paralysis in infants undergoing ligation of patent ductus arteriosus. Annals of Thoracic Surgery 1996;61:814-6.

Other published versions of this review

Malviya

Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 3, 2003.

Comparisons and data

Comparison or outcome Studies Participants Statistical method Effect size
01 Surgical versus medical treatment with indomethacin
01 Death before discharge 1 154 RR (fixed), 95% CI 0.67 [0.34, 1.31]
02 Failure of ductal closure 1 154 RR (fixed), 95% CI 0.04 [0.01, 0.27]
03 Chronic lung disease 1 154 RR (fixed), 95% CI 1.28 [0.83, 1.98]
04 Intraventricular hemorrhage 1 154 RR (fixed), 95% CI 0.83 [0.32, 2.18]
05 NEC 1 154 RR (fixed), 95% CI 0.95 [0.29, 3.15]
06 Creatinine level > 1.8 mg / dl 1 154 RR (fixed), 95% CI 0.57 [0.14, 2.30]
07 ROP grade III and IV 1 154 RR (fixed), 95% CI 3.80 [1.12, 12.93]
08 Pneumothorax 1 154 RR (fixed), 95% CI 2.68 [1.45, 4.93]
09 Sepsis 1 154 RR (fixed), 95% CI 1.14 [0.62, 2.09]
10 Other bleeding 1 154 RR (fixed), 95% CI 1.54 [0.68, 3.51]

 

01 Surgical versus medical treatment with indomethacin

01.01 Death before discharge

01.02 Failure of ductal closure

01.03 Chronic lung disease

01.04 Intraventricular hemorrhage

01.05 NEC

01.06 Creatinine level > 1.8 mg / dl

01.07 ROP grade III and IV

01.08 Pneumothorax

01.09 Sepsis

01.10 Other bleeding

Contact details for co-reviewers

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

Dr Sachin S Shah, MBBS, MD, DM
Director
Neonatal and Pediatric Intensive Care Services
Aditya Birla Memorial Hospital
Office no. 2, Arihant Building
39/32 Karve Road
Pune
INDIA
411004
Telephone 1: 91 20 30717644
Facsimile: 91 20 27277003
E-mail: sshahdoc@hotmail.com
Secondary address:
39/32 Karve Road
1st Floor, Arihant Building
Pune INDIA
411004
Telephone: 91 20 25442244
This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2008 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.