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Paediatr Child Health. Mar 2012; 17(3): 125–128.
PMCID: PMC3287088
Does primary surgical closure of the patent ductus arteriosus in infants <1500 g or ≤32 weeks’ gestation reduce the incidence of necrotizing enterocolitis?
Wendy H Yee, MD,1,2 Jeanne Scotland, NNP,2 and Evidence-based Practice for Improving Quality (EPIQ) Evidence Review Group
1Department of Paediatrics, University of Calgary;
2Alberta Health Services, Calgary, Alberta
Correspondence: Dr Wendy H Yee, Department of Paediatrics, University of Calgary, Unit 63, 7007 14 Street Southwest, Calgary, Alberta T2V 1P9. Telephone 403-943-3424, fax 403-212-1243, email wendy.yee/at/albertahealthservices.ca.
Accepted October 26, 2011.
BACKGROUND:
The hemodynamic perturbation related to patent ductus arteriosus (PDA) is associated with a higher risk of necrotizing enterocolitis (NEC).
OBJECTIVE:
To determine whether primary surgical closure, as compared with treatment with indomethacin or exposure to prophylactic indomethacin, reduces the incidence of NEC in preterm infants <1500 g and/or ≤32 weeks’ gestation with clinically and echocardiogram-identified PDA.
METHODS:
The literature was reviewed using the methodology for systematic reviews for the Consensus of Science adapted from the American Heart Association’s International Liaison Committee on Resuscitation.
RESULTS:
Ten studies were reviewed. The incidence of NEC was not lower in infants who underwent primary surgery for closure of the PDA compared with infants treated with indomethacin or infants exposed to prophylactic indomethacin (level of evidence 2).
CONCLUSION:
Primary surgical closure of the PDA cannot be recommended as an intervention to decrease the incidence of NEC in infants <1500 g and/or ≤32 weeks’ gestation.
Keywords: Necrotizing enterocolitis, Patent ductus arteriosus, Preterm infant, Primary surgery
HISTORIQUE :
La perturbation hémodynamique liée à la persistance du canal artériel (PCA) s’associe à un risque plus élevé d’entérocolite nécrosante (ECN).
OBJECTIF :
Déterminer si la fermeture chirurgicale primaire par rapport au traitement à l’indométhacine ou à l’exposition à une prophylaxie à l’indométhacine réduit l’incidence d’ECN chez les prématurés de moins de 1 500 g ou d’un maximum de 32 semaines d’âge gestationnel ayant une PCA diagnostiquée sur le plan clinique et par échocardiogramme.
MÉTHODOLOGIE :
Les chercheurs ont analysé les publications au moyen de la méthodologie des analyses systématiques pour le Consensus of Science adaptées du comité de liaison internationale sur la réanimation de l’American Heart Association.
RÉSULTATS :
Les chercheurs ont analysé dix études. L’incidence d’ECN n’était pas plus faible chez les nourrissons qui avaient subi une chirurgie primaire pour fermer une PCA que chez les nourrissons traités à l’indométhacine ou exposés à une prophylaxie à l’indométhacine (qualité des preuves 2).
CONCLUSION :
La fermeture chirurgicale primaire de la PCA ne peut être recommandée pour réduire l’incidence d’ECN chez les nourrissons de moins de 1 500 g ou d’un maximum de 32 semaines d’âge gestationnel.
Developed and established in Canadian neonatal intensive care units, EPIQ (Evidence-based Practice for Improving Quality) is a scientific method for continuous quality improvement that is evidence-based; targeted on key outcomes; collaborative, involving interprofessional teams of experts; and continuous, promoting a culture of change. Based on the International Liaison Committee on Resuscitation literature review template, the EPIQ review process addresses important clinical questions by summarizing relevant studies. They are intended as guides to best practices and do not represent unique or mandatory protocols. Full versions of these reviews are available at www.epiq.ca.
Khalid Aziz MD, Assistant Editor, Paediatrics & Child Health
Necrotizing enterocolitis (NEC) is a common morbidity associated with high mortality in very low birth weight (BW) preterm infants (1,2). This population of infants has a high incidence of patent ductus arteriosus (PDA) (3), and it has been suggested that the hemodynamic perturbation (4,5) resulting from this condition is associated with higher risk of NEC (6,7).
OBJECTIVE
We reviewed the literature to determine whether primary surgical closure (without prior indomethacin exposure) for treatment of a clinically and echocardiogram-identified PDA reduces the incidence of NEC, compared with treatment with indomethacin or exposure to prophylactic indomethacin in preterm infants <1500 g BW and/or ≤32 weeks’ gestation.
Key words selected with synonyms were: 1) “patent ductus arteriosus” OR “ductus arteriosus” OR “PDA”; 2) “preterm” OR “premature infant” OR “neonate” OR “newborn”; 3) “necrotizing enterocolitis” OR “NEC”; 4) “surgical ligation patent ductus arteriosus” OR “surgery patent ductus arteriosus” OR “surgery ductus arteriosus” OR “surgery pda”. These concepts were combined with the Boolean operator “AND”. Exclusion criteria were nonhuman subjects, non-English language, abstract only, review articles, children/adult subjects, >32 weeks’ gestation and >1500 grams BW.
Databases searched were Ovid Medline 1950 – 2011, Scopus 1997 – 2009, Web of Science 1997 – 2009, Embase 1987 – 2008, PubMed 1975 – 2011, CINAHL 1996 – 2011, Central Register of Controlled Trials Cochrane 1st Quarter 2011 and Cochrane Database of Systematic Reviews 1st Quarter 2011. The authors reviewed the abstracts of all available reports and studies, including single-centre case series, observational studies with historical and other centre controls, and randomized controlled trials (RCT). The bibliographies of all selected articles and review articles were manually searched for additional studies.
From an initial review of 555 citations and 65 full-text articles (Figure 1), 10 studies were eligible for inclusion in the present review. They were scored using the Evidence Evaluation Worksheet adapted from the American Heart Association’s International Liaison Committee on Resuscitation (ILCOR) <www.american-heart.org/presenter.jhtml?identifier=3052119> (8). Two reviewers independently assigned level of evidence (LOE), direction of support and quality <www.cebm.net/index.aspx?o=1157> (9). Inconsistencies were resolved by consensus.
Figure 1)
Figure 1)
Flow diagram of study selection. NEC Necrotizing enterocolitis; PDA Patent ductus arteriosus
The process for selection of the studies is outlined in Figure 1. Two studies were published before 1990, all other studies were published between 2001 and 2009.
A single-centre RCT (LOE 1) published in 1989 addressed prophylactic surgical ligation of the PDA (10). Subjects with BW <1000 g were randomly assigned to prophylactic surgical ligation of a PDA within 24 h of birth or medical care. The incidence of NEC was higher in the control group compared with the surgery group (13 of 44 versus three of 40, P=0.002), but there was no difference in the outcomes of severe intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), retinopathy of prematurity or death. Mosalli et al (11) reviewed this RCT in their Cochrane systematic review.
Other studies examining the relationship between primary surgical closure of the PDA and the development of NEC in preterm infants were observational, reporting the experience of centres using nonrandomized, concurrent controls for comparison (LOE 2). The studies varied in the first-line treatment with medical management, indomethacin treatment or indomethacin prophylaxis.
Five studies (n=918) used indomethacin as first-line treatment or after failed medical therapy (1216). Within each of these studies, there was a group of infants who underwent primary surgery (without any prior exposure to indomethacin) for a clinically and echocardiogram-identified PDA, allowing for comparison with an indomethacin treated group. Most studies also described a group treated with secondary surgery. These observational studies were within single centres (1215) or two centres (16) (Table 1).
TABLE 1
TABLE 1
Retrospective observational studies comparing outcome of necrotizing enterocolitis (NEC) among groups treated for patent ductus arteriosus (PDA)
One study (13) reported a statistically nonsignificant trend toward less NEC in the primary surgery group compared with a medical treatment group and an indomethacin treatment group. There were only three cases of NEC in this small sample (n=57), an incidence of 5.2%. Four studies (12,1416) reported comparison between two groups: indomethacin treatment and primary surgery. Two of the studies (14,15) did not show a statistically significant difference in NEC outcome between the two groups. One study (12) reported a higher incidence of the combined outcome of NEC and spontaneous intestinal perforation (SIP) in the indomethacin treatment group. The fourth study (16), published in 1987, showed a statistically significant increase in NEC in the primary surgery group.
In a retrospective study that used the database of a multicentre health care provider group (n=12,581) (17), comparison was made among five groups: prophylactic indomethacin, indomethacin treatment, primary surgery, PDA without treatment and no PDA. There was no difference in the incidence of NEC across the groups, except for the comparison between the primary surgery and no PDA groups (Table 1).
Two other studies were pertinent to our review question. A study (18) using regression models on data from the National Institute of Child Health and Human Development (n=2383) showed no difference in the adjusted risk of NEC (OR 1.22 [98.3% CI 0.67 to 2.24]) between the indomethacin treatment group and the primary surgery group; acknowledging that 13% of the surgery group was exposed to prophylactic indomethacin (LOE 2). Compared with indomethacin treatment, infants undergoing primary surgery were at increased risk of BPD (OR 2.19 [98.3% CI 1.16 to 4.15]) and borderline increased risk of neurodevelopmental impairment at 18 to 22 months of age (OR 1.79 [98.3% CI 0.998 to 3.21]). Chorne et al (19) reviewed infants <28 weeks’ gestational age (GA) (n=446) from a single centre, who were all exposed to prophylactic indomethacin. Using multivariable regression analysis to investigate potential predictors of adverse outcomes, controlling for GA and neonatal morbidities, none of the treatment variables, including primary PDA ligation or indomethacin treatment, were predictive for development of NEC (LOE 2). The authors suggested that primary PDA ligation was associated with increased risk of chronic lung disease (CLD).
Quality of the studies
The studies were only of fair quality, and were limited by lack of clear description of the comparison groups, clearly defined outcomes, and known confounders identified and controlled for <www.cebm.net/index.aspx?o=1157>.
The prophylactic surgery study (10) had very high mortality, approximately 60% in both study groups, reflective of outcomes in the presurfactant era. Also, the 30% incidence of NEC in the control group was higher than reported in current populations (1,2).
The other presurfactant era study (16) reported a higher incidence of NEC in the primary surgery group. The surgical infants were smaller in weight, but other baseline characteristics were not described; therefore, it is possible that these were sicker infants who were selected for surgery. In the studies that did not demonstrate a statistically significant difference in the outcome of NEC, the major confounders identified were that the primary surgery group of infants tended to have lower BW and younger GA, as well as having higher incidence of pretreatment IVH, which was the most common contraindication to treatment with indomethacin (1214,17). These confounders were not controlled for in the study analyses, likely due to the small sample size in most of the studies. Hemodynamic significance of the PDA as assessed by echocardiogram was not quantified or adjusted for in any of the studies.
One study (15) identified SIP separately and reported an incidence of approximately 3% across groups. Another study (17), reported an intestinal perforation incidence of 1% in patients without PDA and 3% in indomethacin-treated patients, compared with 6% in patients undergoing primary ligaton. Other studies did not differentiate between these two outcomes. Only one study (12) reported a statistically significant higher incidence of the combined outcome of NEC and SIP in the indomethacin group, compared with the primary surgery group. The study also reported, in the surgical group, an overall reduced risk of the combined complications of NEC/SIP, IVH, thrombocytopenia and acute renal failure, thus favouring primary surgical ligation. Conversely, Laughon et al (17) reported that IVH, retinopathy of prematurity, CLD and mortality were ‘most common’ among the primary surgery group, who were smaller and less mature.
The recurrent confounders in these studies were that patients selected for primary PDA surgery were of lower BW and younger GA, and had higher incidence of pretreatment IVH. The hemodynamic significance of the PDA was not quantified, a confounder that could be addressed in future studies (20). Inclusion of NEC and SIP in some of the studies may have resulted in misclassification bias in the NEC outcome. All of these factors likely contribute to the disparate results of the studies. The database studies, with larger numbers of patients, were not able to demonstrate an advantage to primary surgery of the PDA compared with indomethacin treatment. There was insufficient information in these studies to review and make any comments on a relationship between the timing of PDA surgery and the development of NEC because the timing of the surgery was variable and often not clearly documented in the studies. Although the primary outcome of interest in the present review was NEC, a few studies suggested that primary surgical ligation may be associated with other adverse outcomes such as BPD/CLD and possibly neurodevelopmental impairment (NDI). The risk for potential NDI requires further study in this patient population.
Consensus on science
Primary surgery for PDA appears to be selectively chosen for infants of lower BW, younger GA and with contraindications to indomethacin therapy. Acknowledging this bias, the incidence of NEC is not lower in infants who undergo primary surgery for closure of the PDA compared with infants treated with indomethacin or infants exposed to prophylactic indomethacin (LOE 2).
RECOMMENDATION
Primary surgical closure of the PDA cannot be recommended as an intervention to decrease the incidence of NEC in infants <1500 g and/or ≤32 weeks’ gestation.
Footnotes
EPIQ EVIDENCE REVIEW GROUP MEMBERS:
Principal investigator: Dr Shoo K Lee, Mount Sinai Hospital, Toronto, Ontario.
Chair: Dr Nalini Singhal, Foothills Medical Centre, Calgary, Alberta.
Members: Dr Kim Dow, Kingston General Hospital, Kingston; Dr Andrew James, The Hospital for Sick Children, Toronto, Ontario; Dr Ibrahim Mohamed, Hôpital Sainte-Justine, Montreal, Quebec; Dr Nicole Rouvinez-Bouali, Children’s Hospital of Eastern Ontario, Ottawa, Ontario; Dr Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan; Dr Vibhuti Shah, Mount Sinai Hospital, Toronto, Ontario.
Principal author: Dr Wendy Yee, Foothills Medical Centre, Calgary, Alberta.
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