Efficacy and Risk for PDA Ligation Uncertain in Meta-analysis

Jenni Laidman

March 17, 2014

Surgical ligation of patent ductus arteriosus (PDA) in newborns was associated with half the mortality risk of treatment with medication but was also associated with increased risks for neurodevelopmental, lung, and retinal deficits, according to a meta-analyses of studies that generally failed to account for confounders or adjust for survival bias.

In research published online March 17 in Pediatrics, Dany E. Weisz, MD, neonatologist, Department of Newborn and Developmental Pediatrics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, and colleagues note that the reason for the decreased mortality and increases in neurodevelopmental impairment (NDI), chronic lung disease (CLD), and severe retinopathy of prematurity (ROP) cannot be determined because only a few studies in the analysis adjusted for survival bias or accounted for confounders such as ventilator dependence, intraventricular hemorrhage, or sepsis.

PDA occurs in nearly half of preterm infants born at less than 32 weeks' gestation. Its management ranges from fluid restriction, to diuretics and ventilation, to the use of cyclooxygenase inhibitors and acetaminophen, to surgical ligation. Ligation is usually considered after medical treatment has failed or when it is contraindicated.

The authors performed meta-analyses on 39 cohort studies and 1 randomized controlled trial involving 32,000 infants born at less than 32 weeks' gestation, comparing surgical ligation with medical treatment for patent ductus arteriosus.

In 3 studies of 3250 participants that looked at NDI in early childhood, surgical ligation was associated with increases in NDI compared with medical treatment, with a pooled adjusted odds ratio (AOR) of 1.54 (95% confidence interval [CI], 1.01 - 2.33; I 2, 44%). Among 4 studies with 6703 participants comparing risk for CLD, ligation was associated with increased risk (pooled AOR, 2.51; 95% CI, 1.98 - 3.18; I 2, 44%). In 3 studies of 3122 participants, ligation was associated with more than double the risk for severe ROP (pooled AOR, 2.23; 95% CI, 1.62 - 3.08; I 2, 37%). However, in 5 studies of 7159 participants, ligation associated with nearly half the risk for death (pooled AOR, 0.54; 95% CI, 0.38 - 0.77; I 2, 39).

However, the authors resist drawing conclusions from the data beyond pointing out the need to improve studies necessary for informed clinical decisions.

"Our review highlights the difficulty faced by clinicians considering surgical ligation. The clinician must navigate literature that reports an association with significant morbidity, albeit fraught with methodologic biases and clinical uncertainty regarding patient selection and the optimal timing for surgery," the authors write.

Dr. Weisz told Medscape Medical News that the increased risk for CLD, ROP, and NDI may be partly a result of patient selection. "The sickest infants are the ones being treated with PDA ligation.... Among preterm infants, those with higher illness severity are at higher risk of these outcomes/morbidities."

The perceived risk for CLD, ROP, and NDI has made neonatologists wary of ligation, Dr. Weisz said. "In Toronto, for example, we have gone from performing over 80 PDA ligations per year in 2006, down to about 20 to 30 annually."

The authors offer several possible explanations for the increased survival odds accompanied by increased NDI risk in the publication. Their results could mean that ligation aids in survival while simultaneously increasing the risk for neurological deficit. Or ligation may improve survival, but infants who are referred for ligation may already be at a higher risk for neurologic deficit. Or ligation may lower mortality only because vulnerable medically treated infants die before they are referred for ligation and NDI is either a confounder or a true effect of ligation.

The authors note that infants who underwent surgical ligation were significantly different at baseline compared with medically treated infants, with both lower gestational age and birth weight.

The authors have disclosed no relevant financial relationships.

Pediatrics. Published online March 17, 2014. Abstract

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