Abbreviations

BPD = Bronchopulmonary dysplasia
CHD = Congenital heart disease
CPAP= Continuous positive air-way pressure
IVH = interventricular hemorrhage
NEC = necrotizing enterocolitis
NICU = Neonatal intensive care unit
PDA = Patent ductus arteriosus
PEEP = positive end expiratory pressure
ROP = retinopathy of prematurity

Introduction

Ductus arteriosus is a vascular connection between the main pulmonary artery and aorta. The ductus arteriosus closes spontaneously in most near- and full-term infants during the first three days of life. However, in preterm infants, it remains patent during the first week of life.¹ Patent ductus arteriosus (PDA) is a common congenital heart defect in preterm infants. The incidence of PDA in preterm infants is increasing due to the improved survival rate of infants born with an extremely low birth weight. Similarly, incidence is inversely proportionate to gestational age; in preterm infant’s = 28 weeks, the incidence is as high as 60 percent.²

The Cochrane review 2008 showed that the available clinical trials were unable to establish an obvious relationship between different neonatal morbidities, whether secondary to the hemodynamic changes that occur with left-to-right shunt through the PDA or to the therapies used to close the PDA.³ In a small randomized controlled trial conducted 25 years ago, the investigators suggested that persistent PDA is associated with increased pulmonary morbidity.⁴

The debate regarding optimum management of patent ductus arteriosus in preterm infants has increased in recent years. The majority of clinicians attempt to close clinically significant PDAs using either indomethacin or ibuprofen. If the PDA does not close or reopens after pharmaceutical therapy, then some clinicians consider surgical closure.⁵ The decision to surgically close a “significant” PDA is complicated by recent experiences, indicating that surgery of any kind in newborns is associated with poor neurodevelopmental outcomes. Some preterm infants seem to be unable to tolerate a PDA ligation, perhaps because of acute physiological changes that are imposed on the cardiovascular system that has adapted to the PDA.^6,7

Current conservative measures that have been adopted by some clinicians include adjustment of the ventilation by reducing inspiratory time, increasing positive end expiratory pressure (PEEP), and fluid restriction.⁸

The objective of this study is to assess the short-term outcome of different PDA treatment modalities in premature infants of = 32 weeks’ gestation.

Methods

This study is a descriptive retrospective chart review. All records of preterm infants of <37 weeks’ gestation admitted to NICU at Hamad Medical Corporation, Qatar, within a five-year time period, January 2003 to December 2007, were reviewed and assessed. The NICU had 8604 admissions within this time period. From those admissions, a total of 495 patients had congenital heart disease. PDA was diagnosed in 82 cases of infants born before 32 weeks.

The initial diagnosis of PDA was based on clinical criteria, which are hemodynamic instability, respiratory instability or a combination of both. The hemodynamic criteria included blood pressure instability, bounding peripheral pulses, poor tissue perfusion, and metabolic acidosis. The respiratory criteria included difficulty in weaning from the ventilator, increased ventilatory support, frequent episodes of apnea, carbon dioxide retention and the occurrence of pulmonary hemorrhage. All these cases underwent a routine confirmation by echocardiography. The size of the PDA was classified into three categories: insignificant or small if the diameter was = 1-1.5mm, moderate if the diameter was = 1.5-3mm, and large if the diameter was = 3mm.⁹ Management modalities were divided into conservative, medical or surgical. The conservative approach included optimizing ventilation, restricting the total fluid intake to 130 ml /kg/day and augmenting positive pressure ventilation. The pharmaceutical intervention included using either intravenous Indomethacin or oral ibuprofen. Patients who failed conservative and pharmaceutical treatment while still clinically compromised were candidates for surgical ligation.

The outcomes were assessed by analyzing the percentage of infants with PDA, modalities of treatment and major adverse outcome of these modalities. The rate of occurrence of NEC (modified Bell staging 1–3),¹⁰ IVH, BPD, ROP and mortality rate were also documented. Data obtained from the patient files were entered into a computerized statistical program (SPSS12®)

This study was approved by the Institutional Review Board. A waiver of informed consent for participation was obtained from the ethical committee, since it is a chart review study.

Results

Study demographic

Treatment modalities in preterm infants

Response of different PDA size to different treatment modalities

Complications related to treatment modalities

Effect of PDA size on neonatal outcome

Adverse outcomes have been significantly influenced by the size of the PDA, where the larger the size, the higher the possibility of developing an adverse outcome (Table 4).

Figure 1

Table (1) Demographic features of the study population =32 weeks

Figure 2

Table (2) Neonatal outcome comparing spontaneous closure versus non spontaneous closure

Figure 3

Table (3) Neonatal outcome in babies’ =32weeks comparing medication versus surgery

Figure 4

Table (4) Effect of PDA size on neonatal outcome = 32 weeks

Figure 5

Figure 1.Response of PDA cases according to different treatment Modalities.

Figure 6

Figure 2. Number of PDA successfully closed according to Size and treatment modality.

Discussion

In preterm infants, patency of the ductus arteriosus may represent a normal physiologic adjustment to allow shunting from either systemic-to-pulmonary circulation (e.g., in the first day of life) or from pulmonary-to-systemic circulation (e.g., in the presence of severe lung disease).¹¹

Several studies have discussed medical and surgical treatment; however, few studies have evaluated the outcome of currently popular conservative treatment, which includes adjusting ventilation and fluid restriction.⁸ The spontaneous closure reported in the current study was 23 percent of affected preterm infants of = 32weeks. This rate is not comparable with the rate reported in the literature by Sophie et al., who reported a spontaneous closure rate of 67 percent of the ductus arteriosus in moderately premature infants.⁸ However, this gap could be narrowed if the author factored in the 13/63 infants (20%) in whom the PDA was not completely closed after medication and closed later spontaneously without need for further courses of medication (late spontaneous closure) to bring the overall rate of spontaneous closure to 39 percent. This rate of spontaneous closure is comparable to the rate reported by Josh and his colleagues. They reported a rate of spontaneous permanent DA closure of >34 percent in extremely low birth weight neonates.¹²

Ronald and his colleagues recommended that the therapies designed to close the ductus arteriosus are contraindicated in some settings and should not be considered a standard of care at any time until these therapies are proven to decrease long-term clinical morbidities in randomized, placebo-controlled trials.¹¹ This is reflected in this study’s results, which showed no significant difference when the medication and surgical approach were used in terms of decreasing all morbidities. On the other hand, when comparing the medication and surgical approach with conservative management, there was a statistically significant reduction in all forms of morbidities. This result is supported by the lack of evidence that the treatment of patent ductus arteriosus results in long-term benefit.¹³

Interestingly, the ROP was significantly increased in those patients who received medication of P value 0.003. This can be explained by the need for prolonged respiratory support while receiving medication. Large PDAs have no protective role in comparison to other PDA size in decreasing morbidities. This can be explained by the fact that these infants were subjected to long-term medical treatment with possible long-standing pathology and hazardous surgical intervention.

Both pharmacologic and surgical treatment options exist for closing a PDA, both of which have their own morbidities. Treatment of a PDA is not gentle and has not been shown to prevent any morbidity associated with prematurity.¹⁴

In conclusion, acknowledging the limitations of this retrospective analysis, the rate of PDA closure achieved with conservative treatment at the center was comparable to the rates previously reported with drug management. This conservative approach resulted in ensuring PDA closure, and it did so without exposing the neonates to potential side effects of drug treatment. Although the result is a retrospective chart review analysis, the authors changed their approach to the treatment of small and moderate PDA by placing more emphasis on the conservative approach before exposing the infants to other active interventions. Further confirmation by way of a properly randomized controlled trial is warranted.