**4. Incidence of PDA in premature infants**

Premature birth prolongs closure as gestational age decreases. As many as 50–70% of infants at <28 weeks of gestation have a moderate-to-large PDA that persists for weeks after birth, whereas most infants born >28 weeks of gestation spontaneously close the ductus within the first week. Among infants >1500 g, spontaneous closure of the ductus occurs within 96 h in 95% of neonates [6]. By contrast, only 34% of extremely low birth weight (ELBW) infants (birth weight ≤ 1000 g) are reported to close the ductus by day 10 of life [6].

Little is known about the natural course of PDA in extremely premature infants due to the use of prophylactic and rescue therapy in modern NICUs. Previous studies in the 1960s and 1970s were limited by a lack of modern imaging techniques and likely only captured audible, hemodynamically significant PDAs [7]. The closest approximation is found by examining infants treated with conservative management of the PDA, in which interventions are held until symptoms of distress meet an established threshold. A large retrospective study using conservative management found that 85% of very low birth weight (VLBW) infants (birth weight ≤ 1500 g) closed the ductus spontaneously before discharge, but it should be noted that infants <26 weeks gestational age took a median of 71 days to close. Thirty-three infants, many of whom had a PDA, were excluded from the study due to death from infection, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and pulmonary hemorrhage [8] (Semberova). Another study found spontaneous ductal closure within the first week in 31% of ELBW infants and 67% in infants greater than 1000 g. For ELBW infants, spontaneous closure was achieved in 47% at a median of 56 days at the time of discharge [8, 9]. Thus, PDA in VLBW and ELBW infants can take weeks to close and may cause morbidity and mortality in this population.

### **5. Consequences of PDA in ELBW infants**

While a very tiny ductus may be safely left untreated, a large ductus can cause pulmonary over-circulation and cardiac failure. A moderate ductus can lead to pulmonary hypertension [10, 11] in the long-term. Even a small ductus is at risk for developing endocarditis [12].

Persistent PDA in ELBW infants with respiratory distress syndrome (RDS) has been linked to numerous pulmonary complications, including increased flow

**43**

**Figure 1.**

*PDA Closure in ELBW Infants: If, When, and How to Do It*

tricular leukomalacia (PVL), cerebral palsy, and death [20–22].

shunting of blood in the ELBW infant is not helpful [24].

**6. Hemodynamic significance of the PDA**

and pressure to the pulmonary vascular bed, increased lung water, decreased lung compliance [13, 14], prolonged ventilation [15], worsening pulmonary disease [16], pulmonary hemorrhage [13–16], severe bronchopulmonary dysplasia (BPD) [17],

Over the first few days, pulmonary vascular resistance drops markedly while the PDA remains large, allowing significant shunting of blood to the pulmonary vascular bed. As blood from the PDA returns to the left atrium, left atrial dilation occurs. The increased LA pressure causes pulmonary edema and symptoms of congestive heart failure. While the body may compensate at first, pulmonary hemorrhage may eventually occur [18, 19]. Besides pulmonary hemorrhage the risks of BPD are increased, as ELBW infants require greater ventilatory support as well as increased oxygen [18, 20]. Although the pathogenesis of BPD is complex, associations between prolonged exposure to a moderate-to-large PDA and BPD have been documented [18, 19]. Additional research further established the association of PDA with systemic complications such as NEC, renal impairment, IVH, periven-

While numerous sequelae have been associated with the presence of a moderateto-large PDA in ELBW infants, it remains unclear whether these are the result of having a PDA or are the natural consequences of prematurity. Previous randomized control trials (RCT) suggest that long-term morbidities are not affected by shortterm exposure to a PDA (3–4 days) [13, 23], however these conclusions are confounded by early spontaneous closure of the PDA, failure to account for differing shunt sizes, and the early use of rescue treatments, or a lack of equipoise, on behalf of the physicians [13]. There is no consensus on the exact consequences of a PDA in the premature infant, but most agree that persistent and significant left-to-right

There is no consensus regarding the definition of a hemodynamically significant PDA (hsPDA), yet it is a key indicator for clinicians when determining whether intervention is needed to close the ductus. Historically, clinical signs have been used as indicators of hsPDA, such as the presence of a systolic murmur, wide pulse pressures,

*Transthoracic echocardiogram (TTE) demonstrating a large, hsPDA in a 3 weeks old ex-24 week ELBW infant. (A) 2D-TTE demonstrating a large PDA between the aorta and the pulmonary artery (PA). (B) Color Doppler demonstrating left to right shunt in the PDA from the aorta to the PA. (C) Severe left atrial (LA) and* 

*left ventricular (LV) enlargement relative to the right atrium (RA) and the right ventricle (RV).*

*DOI: http://dx.doi.org/10.5772/intechopen.88857*

and death [17].

*Update on Critical Issues on Infant and Neonatal Care*

**4. Incidence of PDA in premature infants**

When a baby takes its first breath, the increased alveolar oxygen content leads to pulmonary vasodilation, resulting in a decreased ratio of pulmonary vascular resistance (RP) to systemic vascular resistance (RS). This drop in RP/RS can reverse the flow of blood across the ductus arteriosus from right-to-left to left-to-right (aorta to PA). At this point, the ductus is exposed to high systemic arterial pO2, which results in vasoconstriction of the ductus arteriosus through mechanisms not fully elucidated [3–5]. A sharp decline in circulating PGE and PGIE along with a rapid increase in pO2 following birth contributes to constriction, and ultimately functional closure of the ductus. Nearly all healthy, term infants achieve functional closure with 24–72 h [2–5]. Eventually, hypoxia and fibrosis cause the inner layers of the ductus to permanently close, leaving only a fibrous remnant called the ligamen-

Premature birth prolongs closure as gestational age decreases. As many as 50–70% of infants at <28 weeks of gestation have a moderate-to-large PDA that persists for weeks after birth, whereas most infants born >28 weeks of gestation spontaneously close the ductus within the first week. Among infants >1500 g, spontaneous closure of the ductus occurs within 96 h in 95% of neonates [6]. By contrast, only 34% of extremely low birth weight (ELBW) infants (birth weight ≤ 1000 g) are reported to close the ductus by day 10 of life [6].

Little is known about the natural course of PDA in extremely premature infants

While a very tiny ductus may be safely left untreated, a large ductus can cause pulmonary over-circulation and cardiac failure. A moderate ductus can lead to pulmonary hypertension [10, 11] in the long-term. Even a small ductus is at risk for

Persistent PDA in ELBW infants with respiratory distress syndrome (RDS) has been linked to numerous pulmonary complications, including increased flow

due to the use of prophylactic and rescue therapy in modern NICUs. Previous studies in the 1960s and 1970s were limited by a lack of modern imaging techniques and likely only captured audible, hemodynamically significant PDAs [7]. The closest approximation is found by examining infants treated with conservative management of the PDA, in which interventions are held until symptoms of distress meet an established threshold. A large retrospective study using conservative management found that 85% of very low birth weight (VLBW) infants (birth weight ≤ 1500 g) closed the ductus spontaneously before discharge, but it should be noted that infants <26 weeks gestational age took a median of 71 days to close. Thirty-three infants, many of whom had a PDA, were excluded from the study due to death from infection, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and pulmonary hemorrhage [8] (Semberova). Another study found spontaneous ductal closure within the first week in 31% of ELBW infants and 67% in infants greater than 1000 g. For ELBW infants, spontaneous closure was achieved in 47% at a median of 56 days at the time of discharge [8, 9]. Thus, PDA in VLBW and ELBW infants can take weeks to close and may cause morbidity and mortality

**3. Normal closure of the ductus**

tum arteriosum.

**42**

in this population.

developing endocarditis [12].

**5. Consequences of PDA in ELBW infants**

and pressure to the pulmonary vascular bed, increased lung water, decreased lung compliance [13, 14], prolonged ventilation [15], worsening pulmonary disease [16], pulmonary hemorrhage [13–16], severe bronchopulmonary dysplasia (BPD) [17], and death [17].

Over the first few days, pulmonary vascular resistance drops markedly while the PDA remains large, allowing significant shunting of blood to the pulmonary vascular bed. As blood from the PDA returns to the left atrium, left atrial dilation occurs. The increased LA pressure causes pulmonary edema and symptoms of congestive heart failure. While the body may compensate at first, pulmonary hemorrhage may eventually occur [18, 19]. Besides pulmonary hemorrhage the risks of BPD are increased, as ELBW infants require greater ventilatory support as well as increased oxygen [18, 20]. Although the pathogenesis of BPD is complex, associations between prolonged exposure to a moderate-to-large PDA and BPD have been documented [18, 19]. Additional research further established the association of PDA with systemic complications such as NEC, renal impairment, IVH, periventricular leukomalacia (PVL), cerebral palsy, and death [20–22].

While numerous sequelae have been associated with the presence of a moderateto-large PDA in ELBW infants, it remains unclear whether these are the result of having a PDA or are the natural consequences of prematurity. Previous randomized control trials (RCT) suggest that long-term morbidities are not affected by shortterm exposure to a PDA (3–4 days) [13, 23], however these conclusions are confounded by early spontaneous closure of the PDA, failure to account for differing shunt sizes, and the early use of rescue treatments, or a lack of equipoise, on behalf of the physicians [13]. There is no consensus on the exact consequences of a PDA in the premature infant, but most agree that persistent and significant left-to-right shunting of blood in the ELBW infant is not helpful [24].
