Description

• The ductus arteriosus (DA) is a muscular vessel that connects the pulmonary artery with the aortic arch during the embryonic period. It allows the shunt of blood from the pulmonary circulation into the systemic circulation (right-to-left shunt).
• Patent ductus arteriosus (PDA) is the failure of the DA to close soon after birth.
• Risk factors for PDA include prematurity, low birth weight, certain genetic syndromes (see “Genetics”), and those with infections (i.e., sepsis).
• PDA may be isolated or as part of a group of complex cardiovascular malformations.
• In preterms born at ≥30 weeks, 90–98% cases will functionally close by the 4th day. If left untreated, a PDA poses an increased risk for endocarditis, pulmonary hypertension, congestive heart failure, and earlier mortality.
• System(s) affected: cardiovascular, pulmonary

Pediatric Considerations
This is a congenital condition; all patients will require medical care from a multidisciplinary team composed of pediatricians and pediatric cardiologists. Most of this text applies to children.

Pregnancy Considerations

• Asymptomatic women with a restrictive (small with little left-to-right shunt) PDA tend to have uncomplicated pregnancies. However, those with nonrestrictive (moderate or large) PDA with left-to-right shunt can have significant decrease of flow through the DA due to lower gestational vascular resistance. In some cases, the direction of the flow can invert, from left-to-right to right-to-left.
• Women with PDA with right-to-left shunt (Eisenmenger syndrome) are advised against undergoing pregnancy due to high risk of morbidity and mortality.

Epidemiology

• Incidence: 2/1,000 in term births and 8/1,000 in premature live births
• Predominant sex: female > male (2:1 in term births)

Etiology and Pathophysiology

• The fetal DA is kept open by low arterial oxygen content, increased resistance in the pulmonary vasculature, and higher levels of vasodilators, especially circulating prostaglandin E2 (PGE₂), which is produced by the placenta.
• At birth, the closure of the DA is induced by:
  • Biochemical factors (1):
    • Increase of systemic blood pressure that decreases the right-to-left shunt
    • Increase of blood oxygen content that is sensed by a cytochrome P450 system and endothelin-1 (ET-1)-producing cells. Increases in ET-1 promote contraction of muscular cells in the DA.
    • Withdrawal of PGE₂ after delivery
  • Structural factors (1):
    • Growth of intimal cushions during the 3rd trimester obliterates the lumen of the DA.
    • Shear stress through the irregular DA lumen promotes remodeling toward obliteration.
    • Intramural hypoxia leads to increased levels of VEGF and TGF-β. These factors simulate the proliferation of endothelial and muscular cells that helps to occlude the DA.
    • Platelet-vessel wall interaction leads to platelet aggregation with some local clustering of leukocytes.
• These simultaneous processes lead to hemodynamic closure of the DA by 24 hours in 50% of full-term neonates, by 48 hours in 90%, and by 72 hours in virtually all healthy term neonates. Permanent anatomic closure is usually achieved in the 2nd or 3rd weeks after birth.
• Ductal closure is delayed in preterm infants, and the risk of PDA is inversely proportional to gestational age.
• PDA can also be part of a complex variety of cardiovascular malformations (see “Commonly Associated Conditions”), some of which may depend on the shunt of blood through the DA for survival.
• In patients with PDA, as the systemic blood pressure increases over the pulmonary one, the direction of the shunt inverts (from right-to-left to left-to-right). In nonrestrictive PDA, this may compromise the output to the systemic circulation, leading to renal failure and necrotizing enterocolitis due to high-output heart failure.
• If the PDA persists long enough, pulmonary hypertension and right ventricular (RV) hypertrophy and left atrial (LA) and left ventricular (LV) dilatation may develop. In most advanced stages, the pulmonary pressure may permanently exceed the systemic one, with reversal of the flow (to right-to-left) through the DA. This is known as Eisenmenger syndrome.

Genetics
Although no genetic cause is identified in most patients, PDA has been associated with certain genetic anomalies (2):

• Trisomy of any of the following chromosomes: 13 (Patau syndrome), 17 (Edwards syndrome), and 21 (Down syndrome)
• Mutations of any of the following genes: CHD7 (CHARGE syndrome), CREBBP (Rubinstein-Taybi syndrome), TFAP2 (Char syndrome), TBX5 (Holt-Oram syndrome), PTPN11 (Noonan syndrome), MYH11 (TAAD/PDA)

Risk Factors

• Premature birth (specially <30 weeks) and/or low birth weight (specially <1 kg)
• Birth at high altitude
• Respiratory distress syndrome
• Congenital rubella infection
• History of sibling with PDA
• Several genetic disorders (see “Genetics”)

General Prevention

Routine prophylaxis of newborns is not recommended because it has not shown to improve mortality and other outcomes.

Commonly Associated Conditions

• PDA-dependent cardiovascular malformations:
  • Coarctation of the aorta
  • Pulmonary valve stenosis/atresia
  • Hypoplastic left heart syndrome
  • Peripheral pulmonary stenosis
  • Interrupted aortic arch
  • Transposition of great arteries
  • Tetralogy of Fallot
• Necrotizing enterocolitis
• Intraventricular hemorrhage
• Retinopathy of prematurity
• Neurodevelopmental impairment
• Bronchopulmonary dysplasia
• Congenital rubella
• Some genetic syndromes (see “Genetics”)