Mechanisms Regulating Closure of the Ductus Arteriosus

Introduction ^a

a Portions of this chapter are reprinted from Chapter 54 in Avery’s Diseases of the Newborn, 10e.

The ductus arteriosus represents a persistence of the terminal portion of the sixth branchial arch. During fetal life, the ductus arteriosus serves to divert blood away from the fluid-filled lungs toward the descending aorta and placenta. After birth, constriction of the ductus arteriosus and obliteration of its lumen separates the pulmonary and systemic circulations. In full-term infants, obliteration of the ductus arteriosus takes place through a process of vasoconstriction and anatomic remodeling. In the preterm, the ductus arteriosus frequently fails to close. The clinical consequences of a patent ductus arteriosus (PDA) are related to the degree of left-to-right shunt through the PDA with its associated change in blood flow to the lungs, kidneys, and intestine.

Diagnosis

Phase contrast magnetic resonance imaging appears to offer the most accurate measurements of ductal shunt volume and the effects of a PDA on left ventricular and systemic blood flow volumes. Unfortunately, these measurements are difficult to obtain in extremely immature, sick preterm infants. As a result, two-dimensional echocardiography and color Doppler flow mapping have been used as the standard for assessing the presence, magnitude, and direction of PDA shunting. Although pulsed Doppler echocardiographic assessments can consistently diagnose the presence of a PDA, determining its hemodynamic significance has been more challenging. Ductus diameter ≥1.5 mm (or >50% of the diameter of the left pulmonary artery), left atrial-to–aortic root (LA/Ao) ratio ≥1.5, reversal of forward blood flow in the descending aorta during diastole, and end diastolic flow velocity in the left pulmonary artery ≥0.20 m/s are signs consistent with a moderate-to-large PDA shunt. ^, Unfortunately, the inter-observer repeatability of all echocardiographic parameters is relatively poor.

Clinical signs of a PDA (systolic murmur, hyperdynamic precordial impulse, full pulses, widened pulse pressure, and/or worsening respiratory status) usually appear later than echocardiographic signs and are less sensitive in determining the degree of left-to-right shunt. Certain signs such as continuous murmur or hyperactive left ventricular impulse are relatively specific for a PDA but lack sensitivity; conversely, worsening respiratory status, while a sensitive indicator, is relatively nonspecific for a PDA. Tachycardia is not a useful or reliable indicator of a PDA in preterm infants. Infants with large left-to-right shunts may have evidence of cardiomegaly and increased pulmonary arterial markings on their chest x-rays; however, in general, the chest x-ray and electrocardiogram are not useful in diagnosing a PDA. Although elevated plasma concentrations of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NTpBNP) have been found to correlate with the presence of a moderate sized left-to-right PDA shunt, changes in BNP and NTpBNP concentrations have poor sensitivity and specificity in predicting increases or decreases in PDA shunt magnitude and cannot be used to replace echocardiography in the management of PDA shunts.

Infants with persistent small PDA shunts appear to have similar neonatal outcomes as infants who close their ductus shortly after birth, whereas infants with moderate and large PDA shunt volumes appear to have increased neonatal morbidity. ^, While PDA shunt magnitude plays a significant role in creating its hemodynamic significance, equally important are the duration of exposure to the shunt and the infant’s ability to compensate for the shunt. Infants with poor ventricular diastolic function and a PDA are more likely to develop morbidities like bronchopulmonary dysplasia (BPD) than infants with normal diastolic function. Similarly, adverse perinatal and neonatal events, lower gestational age, and the degree of respiratory support that an infant requires all contribute to exacerbating detrimental effects of a PDA shunt. At this time, a consistent definition of hemodynamically significant PDA, which includes both markers of shunt volume and clinical characteristics, has yet to be agreed upon.

Incidence

Pulsed Doppler echocardiographic assessments of full-term infants indicate that functional closure of the ductus has occurred in almost 50% by 24 hours, in 90% by 48 hours, and in all by 72 hours. Ductus closure is delayed in preterm infants; however, essentially all healthy preterm infants (and 90% of those with respiratory distress syndrome) who are at least 30 weeks gestation will close their ductus by the fourth day after birth. Infants born at less than 30 weeks gestation have a 65% incidence of persistent ductus patency beyond day 4 ( Table 52.1 ). Even among the most immature infants (≤27 weeks gestation), spontaneous closure can occur during the neonatal period. However, when it does occur, it usually occurs late during the neonatal course (average age 61 ± 37 days). Eighty-six percent of preterm infants with a persistent PDA at the time of discharge from the hospital will close their PDA by 1 year of age. The remainder will require continued observation or transcatheter device closure.

Several prenatal and postnatal factors also appear to alter the incidence of PDA in preterm infants. Chorioamnionitis increases the incidence of PDA; however, its effects may depend more on its ability to induce preterm birth than its effect on ductus pathobiology. Surfactant administration can lead to early clinical presentation of the left-to-right shunt by altering pulmonary vascular resistance, even though it has no direct effect on ductus contractile behavior. ^, Infants who have late-onset septicemia or receive excessive fluid administration during the first days of life also are more likely to develop a clinically symptomatic PDA. Small-for-gestational age infants delivered between 23 and 24 weeks have a decreased risk of PDA, while those delivered at 26 to 29 weeks have an increased risk. Non-Caucasian infants and infants who receive antenatal glucocorticoids have a reduced risk of PDA.