Pathophysiology

The ductus arteriosus (DA) is important in foetal circulation as it stops the blood from reaching the non-functional foetal lungs by connecting the main pulmonary artery and the descending aorta, allowing blood with a low oxygen concentration to flow through the descending aorta to the placenta, for gas exchange. Ninety percentage of right ventricular output flows through the DA before birth. ^{Reference Dice and Bhatia3} The patency of the foetal DA is maintained by the low foetal oxygen tension and the action of COX enzymes in forming circulating prostaglandins that vasodilate the ductus arteriosus. DA smooth muscle relaxation is the result of the activation of G-coupled prostaglandin receptor EP4 by PGE₂, the most common product of arachidonic acid metabolism. The activation of EP4 leads to the build-up of cyclic adenosine monophosphate, a low myosin light-chain kinase and an increase in protein kinase A, which cause vasodilation and ultimately DA patency. In the final period of gestation, smooth muscle cells within the DA migrate and form a round mass known as the intimal cushions towards the endothelial lining. At birth, a sudden decrease in prostaglandin levels caused the constriction of the DA, by the merging of the intimal cushions to obstruct the DA lumen. ^{Reference Smith4} The ductus in a preterm foetus is even more sensitive to the effects of prostaglandins in vasodilation, therefore increasing the risk of ductal closure failure. On the other hand, term infants have a decreased sensitivity of the DA to prostaglandins and decreased circulating levels of PGE2 contribute to DA closure. ^{Reference Clyman, Mauray, Rudolph and Heymann5} Patent ductus arteriosus is when the ductus arteriosus fails to close after birth, consequently, leading to the formation of a left-to-right shunt, since the blood pressure in the aorta is much higher than the pulmonary artery. Patency increases the pressure inside the pulmonary circuit leading to pulmonary hypertension, which causes arrhythmias and congestive heart failure. Patent ductus arteriosus could sometimes be induced to produce a positive outcome in children born with life-threatening congenital heart defects, for example, in children born with a transposition of the great vessels, where PDA can help maintain circulation. This is useful as it allows surgeons time to prepare for surgery. ^{Reference Huff, Chaudhry, Arora and Mahajan6}

Presentation of patent ductus arteriosus

The clinical presentation of PDA is dependent upon the size of the DA and gestational age.

Infants with a small PDA can remain asymptomatic or may take some time for symptoms to progressively develop. The symptoms of PDA are mainly due to the left-to-right (aortic- pulmonary) shunt, resulting in excessive perfusion of the pulmonary vasculature. The progressive congestion ultimately causes respiratory failure and the lack of systemic perfusion results in end-organ damage. End-organ damage manifests as renal failure, in addition, infants may also develop feeding intolerance, necrotizing enterocolitis, intraventricular haemorrhage, periventricular leukomalacia, and cerebral palsy. ^{Reference Drougia, Giapros and Krallis7} Infants present with episodes of apnoea, signs of heart failure such as tachypnoea, dyspnoea with feeding, tachycardia, bounding pulse, and wide pulse pressure. ^{Reference Mitra, de Boode, Weisz and Shah8} The infant progressively develops chronic lung disease and congestive heart failure requiring ventilator. ^{Reference Gillam-Krakauer and Mahajan9}

Risks of persistent patent ductus arteriosus

A persistent PDA in neonates and infants has historically been correlated with increased morbidity and mortality risks at 30%, with an increased incidence in preterm infants in comparison to their term counterparts, ranging from 20 to 60%. ^{Reference Dice and Bhatia3}

The physiological sequelae of a persistent PDA are well established, such as bronchopulmonary dysplasia (BPD), chronic lung disease (CLD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), heart failure, infective endocarditis, intraventricular haemorrhage, osteopenia, renal impairment, direct hyperbilirubinemia, and delayed growth (Table 2). Furthermore, there is an increase in the duration of mechanical ventilation, stay in hospital and use of oxygen therapy and parenteral nutrition, and tracheostomy whilst in hospital. ^{Reference Saldeño, Favareto and Mirpuri10}

A review reported that at follow-up, there was an increased association of CLD, neurodevelopmental impairment (NDI), and ROP amongst infants who underwent surgical ligation as opposed to the persistent PDA that were treated more conservatively. ^{Reference McNamara and Weisz11}

The extent of haemodynamic stability, gestational age, and birth weight seem to be pertinent factors in regard to clinical assessment of whether surgical interventions such as ligation or more conservative, “watchful waiting” and pharmacological management is required

Evidence from more recent studies indicates that there is eventual spontaneous closure in 80% of non-ligated infants, although the median age of closure is 42 days in comparison to 28 days in ligated infants. This suggests that where haemodynamically appropriate, persistent patency may be of a long-term benefit if surgical intervention and its subsequent complications can be avoided. ^{Reference Sankar, Bhombal and Benitz12} However, in the correct clinical context, such as in the instance of systemic and pulmonary duct-dependent cardiac defects, maintaining patency of the DA is of utmost importance and may be lifesaving. ^{Reference Deshpande, Baczynski, McNamara and Jain13}

Interventions for persistent patent ductus arteriosus

Management options for a patent PDA can be medical or surgical. Indications for management include the onset of symptoms including respiratory compromise, concomitant heart failure, or a large left-to-right ductus shunt. As summarised in Table 3, various medical and surgical techniques have different risks and long-term outcomes.

When to keep PDA open

Usually if the DA fails to close after birth, medical management can help facilitate closure. However, certain duct-dependent flow defects rely on a patent DA for survival. These defects are termed critical congenital heart defects. The presence of central shunts (ductus arteriosus, ductus venosus, and foramen ovale) is important for effective fetal and postnatal circulation. Most patients with such defects have severely hypoplastic right or left ventricles and/or severe obstructive valvular or outflow tract defects. Presentation with dyspnoea and cyanosis will typically occur within hours or days after birth. Examples of right-to-left shunt lesions can include tetralogy of Fallot, pulmonary atresia with ventricular septal defect, Ebstein’s anomaly, or defect with severe pulmonary stenosis or pulmonary atresia. Similarly, left-sided obstructive lesions requiring a patent ductus arteriosus for survival include hypoplastic left heart syndrome, severe aortic valve stenosis, coarctation of aorta, or defect with systemic outflow obstruction.

Whilst initially, medical management with prostaglandin E1 infusions can help keep the DA open, stents can be inserted for longer duration effect. These are largely used in the palliative care setting.

Keeping the DA open in such congenital heart defects is the only means of blood supply to the body. For instance, in pulmonary atresia, there is reduced or absent blood flow from the right ventricle to the pulmonary circulation and so a patent foramen ovale and ductus arteriosus allows for shunting of blood across the atria and pulmonary circulation respectively for survival.

Future research

Although there are several interventions available for the management of PDA, the majority of the studies compared only two interventions. Therefore, a future RCT that includes all interventions would aid in decision-making for clinicians. Future studies are also needed to ascertain which infants are at greater risk of persistent PDA and which specific treatment they require. Essentially defining the higher risk category in terms of clinical and genetic profile and subsequent indications.

Studies should also use similar definitions for symptomatic PDA, interventions, indications for interactions, and what constitutes successful treatment of PDA looking at long-term outcomes. Finally, in terms of quality, the evidence should be evaluated using tools such as Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for more objective comparisons.