INTRODUCTION — In the fetus, the ductus arteriosus (DA) is an important vascular connection between the main pulmonary artery and the aorta (figure 1) that diverts blood from the pulmonary artery into the aorta, thereby bypassing the lungs. After birth, the DA undergoes active constriction and eventual obliteration. A patent ductus arteriosus (PDA) occurs when the ductus fails to completely close after delivery. PDA occurs commonly in preterm infants, especially in those with respiratory distress syndrome.
The pathophysiology, clinical features, and diagnosis of PDA in preterm infants are reviewed here. The management of PDA in preterm infants, as well as the diagnosis and treatment of PDA in older infants and children, are discussed separately. (See "Patent ductus arteriosus in preterm infants: Management" and "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults".)
FETAL AND TRANSITIONAL DUCTAL CIRCULATION
Circulatory transition at birth — In the fetus, the right ventricle accommodates approximately 65 percent of the total cardiac output. The pulmonary vasculature is constricted, resulting in a high vascular resistance within the pulmonary bed. In contrast, the placenta creates a very low resistance bed arising from the aorta, and systemic vascular resistance is low. As a result, the majority of blood exiting from the right ventricle passes right-to-left across the ductus arteriosus (DA) into the descending aorta and onto the placenta (figure 2 and figure 3). (See "Physiologic transition from intrauterine to extrauterine life", section on 'Fetus'.)
With the onset of respiration after delivery, the lungs expand and the systemic oxygen saturation rises, resulting in pulmonary vasodilatation and a drop in pulmonary vascular resistance. At the same time, systemic resistance rises with placental removal. These factors lead to a sudden reversal of blood flow in the DA from right-to-left to left-to-right shunting with concomitant increase in left ventricular output [1]. (See "Physiologic transition from intrauterine to extrauterine life", section on 'Transition at delivery'.)
Patency of the ductus — The fetal ductus is kept patent by low arterial oxygen content and has a diameter similar in size to that of the descending aorta (figure 1) [2]. Ductal patency also is influenced by vasodilators, including prostaglandins and nitric oxide.
At birth, the rise in systemic oxygen tension with the onset of breathing results in active constriction of the ductus, although the mechanisms for this response are not fully understood. In addition, circulating levels of the vasodilator prostaglandin E2 are decreased after delivery because of both reduced production following removal of the placenta and increased pulmonary clearance [3]. The predominance of constricting agents results in ductal constriction. (See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults", section on 'Ductal constriction'.)
The role of prostaglandins in maintaining ductal patency provides the rationale for the use of inhibitors of prostaglandin synthesis (eg, indomethacin and ibuprofen) in the treatment of PDA. antenatal administration of indomethacin also can induce intrauterine ductal constriction. In two case series, fetal echocardiography detected ductal constriction in approximately one-half of the fetuses whose mothers received antenatal indomethacin treatment [4,5]. In one of these reports, ductal constriction occurred in 70 percent of fetuses after 31 weeks gestation and was reversed with discontinuation of the drug [5]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)
Permanent closure — The initial sustained constriction of the ductus is the first step in permanent anatomic closure. The closure is thought to begin at the pulmonary end of the ductus and proceeds toward the aortic end [6].
Gestational age (GA) has a major impact upon the rate of ductal closure:
●Term infants – At term, constriction of the ductus results in functional hemodynamic closure in 50 percent of infants within 24 hours after birth, in 90 percent at 48 hours, and in virtually all patients after 72 hours [7]. (See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults", section on 'Ductal constriction'.)
●Preterm infants – Ductal closure is delayed in preterm infants and the risk of PDA is inversely proportional to GA. The higher incidence of PDA in preterm infants may be explained by the effect of prematurity on the regulators of ductal tone (eg, oxygen) [8-11].
Complete anatomic closure usually takes two to three weeks but may take up to several months. Following initial functional constriction, the proliferation and infolding of endothelial cells and migration of undifferentiated smooth muscle cells result in the obliteration of the ductal lumen and conversion to the ligamentum arteriosum [8,12]. These histologic changes depend upon the initial ductal constriction and the resultant hypoxia within the ductal wall. Hypoxia of the inner vessel wall causes loss of cells from the muscle media and production of vascular endothelial growth factor (VEGF). VEGF stimulates endothelial cell proliferation that leads to formation of mounds in the intima that occlude the lumen [9,13-15].
Reopening — The histologic changes following constriction of the DA occur rapidly in term infants and prevent subsequent reopening. However, in preterm infants, the ductus can reopen after closure that occurs either spontaneously or following indomethacin treatment [16,17]. The reopening of the DA may be due to the same effects of prematurity that blunt the ductal response to factors that promote initial constriction at the time of delivery. In one study of 77 preterm infants who had complete clinical closure of a PDA after indomethacin treatment, a clinically significant PDA recurred in 23 percent of the patients [18]. The rate of reopening increased with decreasing GA, occurring more frequently in infants less than 27 weeks gestation than in those 27 to 33 weeks (37 versus 11 percent).
CONSEQUENCES OF A PDA
Overview — Blood flow through a PDA in preterm infants results in a left-to-right shunting of blood from the aorta into the pulmonary arteries leading to increased flow through the pulmonary circulation and potential hypoperfusion of the systemic circulation. Radionuclide studies demonstrate pulmonary blood flow can be up to three times greater than that of the systemic blood flow [19]. The physiologic consequences of this "ductal steal" depend upon the size of the shunt and the response of the heart, lungs, and other organs to the shunt. It should be noted that shunting through the ductus arteriosus is normal during fetal life and is important during the transition at birth. In instances where there is persistent pulmonary hypertension, the ductus can relieve excess stress on the heart by shunting blood right-to-left from the pulmonary artery to the aorta. In cases of ductal-dependent congenital heart disease the ductus is vital for supporting circulation and reducing the right ventricular afterload. However, there may be deleterious effects of a PDA when there is excessive left-to-right shunting from the aorta into the pulmonary artery with resulting pulmonary overcirculation and reduced systemic perfusion with significant shunting.
Clinically meaningful findings are due to a hemodynamically significant PDA (see 'Hemodynamically significant PDA' below) and include the following:
●Pulmonary edema
●Pulmonary hemorrhage
●Bronchopulmonary dysplasia (BPD)
●Intraventricular hemorrhage (IVH)
●Necrotizing enterocolitis (NEC)
Pulmonary effects — In preterm infants, a symptomatic PDA is associated with increased risk of pulmonary edema, pulmonary hemorrhage, bronchopulmonary dysplasia, and a decrease in pulmonary function. PDA closure eliminates the left-to-right shunting of blood and improves pulmonary compliance and ventilation [20-23]. (See 'Hemodynamically significant PDA' below.)
●Pulmonary edema — Infants with PDA are at risk for pulmonary edema. Proposed underlying mechanisms include increased filtration of lung fluid into the interstitium from increased pulmonary blood flow and/or increased left atrial pressure loading with secondary pulmonary venous hypertension (image 1).
●Pulmonary hemorrhage — Larger PDAs with increased pulmonary blood flow and ductal shunting are associated with pulmonary hemorrhage. In a study of 126 infants born before 30 weeks gestation, 12 patients with pulmonary hemorrhage compared with those without pulmonary hemorrhage had greater median PDA diameter (2 versus 0.5 mm) and pulmonary blood flow (326 versus 237 mL/kg per minute) [24]. Ductal diameter measured at five hours of age also was greater in the infants who subsequently developed pulmonary hemorrhage.
●Bronchopulmonary dysplasia — A hemodynamically significant PDA may be associated with the development of subsequent BPD [25-27].
Support for the role of PDA in the development of BPD was provided by a large case series of 865 very low birth weight (VLBW) infants (BW <1500 g) who survived to 36 weeks postmenstrual age [27]. A diagnosis of PDA in the first week after birth was associated with a 4.5-fold increase in BPD [27]. The risk of BPD and long-term pulmonary sequelae may be related to the duration of ductal patency, even when the PDA is asymptomatic [28,29]. (See "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features".)
Additional evidence regarding the association with hemodynamically significant PDA and BPD were provided by the following:
•A retrospective cohort study of preterm infants (GA <28 weeks) reported symptomatic infants at-risk for BPD (eg, ventilator-dependent) were more likely to undergo surgical ligation [30].
•A smaller case series of VLBW infants (BW <1500 g), surgical ligation was associated with respiratory improvement for infants who received high-frequency ventilation [31].
•Prophylactic indomethacin provided in the first week of life compared with conservative management was associated with a lower incidence of PDA and duration of moderate to large PDA. Multivariate analysis also demonstrated a decreased risk of BPD and BPD or death for infants who received prophylactic indomethacin compared with those with conservative treatment [32].
In contrast, data from the Trial of Indomethacin Prophylaxis in Preterms (TIPP) demonstrated that prophylactic intervention to prevent PDA did not decrease the incidence of BPD [33]. A re-examination of the only trial of prophylactic ductal ligation actually showed a higher risk of BPD in the ligated infants [34]. Thus, while it would be logical to assume that PDA may be a contributing factor to the development of BPD because of the strong association between the two, such a causal link has not fully been established and may not exist.
Systemic and cerebral blood flow effects — Although preterm infants with a PDA have an increased cardiac output, the postductal blood flow is reduced because of left-to-right shunting. Moderate and large ductal steals in infants with PDA result in reduced oxygen delivery and perfusion to vital organs and may contribute to an increased risk of IVH and NEC.
●Intraventricular hemorrhage — Moderate or large left-to-right shunts may increase the risk of IVH. Late IVH (occurring after 24 hours of life) is thought to result from ischemia-reperfusion injury due to cardiac output that is initially low followed by rapid augmentation when pulmonary vascular resistance (PVR) falls [35]. Infants with significant PDAs also have reduced cerebral blood flow and oxygenation, but data are lacking demonstrating an association of these findings with IVH [36,37].
Data from the TIPP study showed the risk of severe IVH was decreased in the group who received prophylactic indomethacin for PDA closure compared with the placebo group (9 versus 13 percent) [38]. However, there was no difference in the rate of neurosensory impairment for survivors in both groups at a corrected age of 18 months.
●Necrotizing enterocolitis — In a study of VLBW infants, the rate of NEC in the prophylactically ligated group was lower than the control group (8 versus 30 percent) [39]. These results may be due to a lower abdominal aortic blood flow in infants due to a significant ductal steal in infants with a hemodynamically significant PDA compared with infants with no or less significant PDAs [39,40]. However, a systematic review of the literature did not observe any difference in NEC rates between prophylactically treated infants and controls [41]. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Circulatory instability'.)
●Hypotension — Moderate or large PDAs are associated with clinically significant hypotension requiring pharmacotherapy intervention [42-44]. In some cases after surgical ligation, hypotension is refractory to vasopressor therapy and may be due to low cortisol levels and impaired vascular tone [45,46].
RISK FACTORS — The risk of PDA increases with decreasing gestational age (GA) and birth weight (BW), and chromosomal abnormalities [47-51]. In very low birth weight (VLBW) infants (BW <1500 g), the incidence of PDA is approximately 30 percent [52]. For healthy infants greater than 30 weeks gestation, the ductus typically closes by the fourth day of life [53]. However, two-thirds of ill infants less than 30 weeks gestation will have a persistent PDA through the fourth day of life and closure is especially delayed for moderate to large PDAs [16,54]. Closure is also less likely to occur in infants who have neonatal respiratory distress syndrome, who did not receive antenatal corticosteroids, who have evidence of metabolic acidosis or with exposure to chorioamnionitis [16,55,56].
CLINICAL FEATURES — The clinical features of PDA are dependent on the magnitude of the shunt. Those with hemodynamically significant PDAs will exhibit findings of pulmonary overcirculation and left heart overload. These patients typically develop signs during the first two to three days after birth. Clinical findings may develop earlier in infants treated with surfactant because the reduction in pulmonary vascular resistance (PVR) associated with improved lung function results in increased left-to-right shunting [57-59]. Heart failure may rarely develop later in the first week. In a few patients, asymptomatic PDA can persist with closure occurring after 10 days of age [16].
Heart murmur — In patients with moderate to large PDAs, cardiac auscultation detects a murmur often heard over the entire precordium, but best heard in the left infraclavicular region and upper left sternal border. At delivery with high PVR, the murmur initially may be heard only in systole because aortic pressure is greater than pulmonary pressure only in systole and not in diastole. As PVR and pulmonary artery pressure (PAP) fall, aortic pressure is higher than PAP during both systole and diastole, producing continuous flow through the ductus and the continuous (machinery) murmur typically associated with a PDA (movie 1).
For patients with a small PDA, a murmur may not be detected. Occasionally, even a larger PDA is clinically "silent" with absence of a murmur, especially in the first three days after birth [60,61]. In these cases, if there is a hemodynamically significant PDA, there may be signs associated with pulmonary overcirculation and left ventricular overload depending on the degree of PVR.
Findings associated with hemodynamically significant PDA — Clinical findings associated with a hemodynamically significant PDA include:
●Signs of increased pulmonary circulation, including tachypnea, apnea, increased carbon dioxide retention, and/or increased requirements for respiratory support including mechanical ventilation. Chest radiography will demonstrate increased pulmonary vascular markings and/or edema (image 1).
●Signs of left ventricular overload include prominent left ventricular impulse and enlarged heart on chest radiograph (image 1).
●Systemic circulatory findings include bounding pulses and a widened pulse pressure that is greater than 25 mmHg or a difference between the systolic and diastolic blood pressure (BP) that exceeds half of the value of the systolic BP. Diastolic BP is typically low.
●Other clinical findings due to poor systemic perfusion include acidosis, oliguria, and abdominal distension.
However, no single finding is specific for a PDA. Similar findings can occur with other cardiac lesions, such as an aortic-pulmonary window or an arteriovenous fistula.
Associated complications — Complications of prematurity that occur more commonly among infants with a hemodynamically significant PDA include (see 'Consequences of a PDA' above):
●Pulmonary edema
●Bronchopulmonary dysplasia (BPD) [34]
●Necrotizing enterocolitis (NEC) [39]
●Heart failure
●Intraventricular hemorrhage (IVH) [38]
●Prolonged ventilator and/or oxygen support
●Acute kidney injury [62,63]
DIAGNOSIS — The diagnosis of PDA is usually suspected by its characteristic clinical findings (see 'Clinical features' above) and confirmed by echocardiography. The combination of two-dimensional echocardiographic imaging and Doppler color flow mapping is both sensitive and specific for the identification of PDA (movie 2 and movie 3) [64].
Echocardiogram — At our institution, an echocardiogram is performed to confirm the presence of a clinically significant PDA before initiating therapy. Other centers, especially those in resource-limited settings without readily available onsite echocardiography, may elect to treat presumptively based on clinical findings. In these settings, echocardiography is performed only if there is a contraindication to the use of indomethacin or ibuprofen therapy, when there is no response to medical therapy, or there is a recurrence of findings after medical therapy. (See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults", section on 'Echocardiography'.)
In preterm infants without a murmur or other physical findings suggestive of PDA, but with an unexplained deterioration in respiratory status, an echocardiogram is necessary to determine whether a "silent" PDA is present. (See 'Clinical features' above.)
Hemodynamically significant PDA — Because the interventions used to close PDA can have significant adverse effects, the decision to intervene should be based upon a hemodynamically significant PDA, which if left untreated leads to pulmonary overcirculation (pulmonary edema), and systemic undercirculation (oliguria and metabolic acidosis ) (see 'Consequences of a PDA' above and 'Associated complications' above).
In our practice, the diagnosis of a hemodynamically significant PDA uses both clinical findings and echocardiographic measurements to classify the severity of PDA and guide management decisions [51,65].
Clinical findings include:
●Need for oxygenation and respiratory support
●Evidence of oliguria
●Presence and degree of acidosis
●Physical findings of wide pulse pressure, suggestive of pulmonary edema (rales)
●Episodes of hypotension requiring pharmacotherapeutic intervention
●Cardiomegaly based on chest radiograph (see 'Chest radiograph' below)
The echocardiographic findings used to define a hemodynamically significant include [51,66]:
●PDA diameter that exceeds 1.4 mm [51,66-69]. However, transductal diameter cannot be used as the sole measure of a significant PDA and measurements of systemic perfusion are also needed [70]. In addition, PDA diameter may need to be adjusted to the relative size of the patient especially in the smallest infants. Adjustments vary amongst centers and include corrections based on body surface area or in relation with the left pulmonary artery diameter [66,70]. A PDA:LPA flow ratio defines large (≥1), moderate (<1 but ≥0.5), and small (<0.5) PDAs (movie 2 and movie 3) [71,72].
●Additional criteria for estimation of systemic perfusion include one or more of the following. However, criteria vary from center to center, although most centers agree that reversed diastolic flow in the descending aorta represents a significant finding of systemic hypoperfusion [66,70]:
•Reversed diastolic flow in the descending aorta.
•Ductus flow velocity ≤2.5 m/sec or mean pressure gradient across the ductus ≤8 mmHg.
•Evaluation of left ventricular output. There is also center variability on how this is measured.
•Assessment of left ventricular output and evidence of left ventricular or atrial hypertrophy.
Several centers have incorporated these findings to develop PDA scoring systems to guide therapeutic decisions (algorithm 1) [51]. These provide a more precise management approach with the use of objective criteria, thereby decreasing the variability in patient care.
Chest radiograph — Chest radiography may be helpful in the diagnosis and evaluation of PDA in preterm infants, but it is less sensitive and specific than echocardiography. In patients with moderate and large PDAs, the chest radiograph shows increasing cardiac enlargement and pulmonary vascular markings as the left-to-right shunting increases (image 1). The electrocardiogram is not helpful in the diagnosis of PDA in preterm infants.
Biomarkers — Biomarkers such as B-type natriuretic peptide (BNP), the inactive N-terminal pro-BNP, and troponin T have been proposed as useful in the diagnosis and management of PDA [73-76]. However, a review of the literature found that the sensitivity and specificity of these tests vary in different populations and sites [77]. As a result, further study is needed prior to the routine use of BNP or other biomarkers to diagnose and manage PDA in preterm infants. In our center, we do not use BNP to make a diagnosis of PDA.
DIFFERENTIAL DIAGNOSIS — Although very uncommon, other diagnoses of continuous murmurs include systemic arteriovenous malformations, fistula, and aortic-pulmonary window. Although very rare, combined aortic stenosis and regurgitation and combined pulmonic stenosis and regurgitation will have murmurs through diastole and systole described as a "to-and-fro" murmur rather than one with a continuous quality as seen in those with a PDA. PDA is distinguished from these conditions based on physical findings (quality and location of the murmur) and echocardiography. (See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults", section on 'Differential diagnosis'.)
SCREENING — Universal screening for PDA in extremely preterm (EPT) infants (gestational age [GA] <28 weeks) has been proposed as a strategy to reduce morbidity and mortality associated with PDA in this population. However, the evidence remains inconclusive. As a result, in our practice, we continue to perform screening echocardiography selectively only if there are clinical signs of PDA.
The impact of universal screening was investigated in a study of 1513 EPT infants from the EPIPAGE 2 cohort, a prospective population-based French study [78]. Screening echocardiogram was performed in 56 percent of patients (n=847), whereas 44 percent (n=666) did not undergo screening. In propensity score analysis, PDA screening was associated with lower in-hospital mortality (14 versus 18 percent; odds ratio [OR] 0.73, 95% CI 0.54 to 0.98) and a lower incidence of pulmonary hemorrhage (5.6 versus 8.9 percent; OR 0.60, 95% CI 0.38 to 0.95). The higher mortality in the non-screened group was primarily observed in untreated infants; however, it is unclear whether all of these patients had a PDA. Rates of NEC, severe BPD, and severe cerebral injury were similar in both groups.
A follow-up study reported neurodevelopmental outcomes at 5.5 years in 71 percent of surviving infants from the original propensity score matched cohort of EPIPAGE 2 [79]. Rates of moderate to severe neurodevelopmental impairment (NDI) were similar in screened and non-screened infants (24 versus 28 percent, respectively). On standardized testing, children in the screened group scored higher on two domains of intelligence, but full-scale intelligence quotients were similar in both groups. There were few deaths in either group after discharge from the initial neonatal hospitalization. Overall, more infants in the screened group survived to age 5.5 years without moderate to severe NDI (65 versus 59 percent), though this finding had borderline statistical significance (OR 1.3, 95% CI 1.0-1.68).
The findings of EPIPAGE 2 are promising; however, given the observational nature of these data, it is possible that some of the observed differences between screened and non-screened infants in these studies may be explained by selection bias. These results should be confirmed in randomized trials before universal screening is adopted into routine clinical practice. In particular, the cost-benefit of universal versus selective screening remains uncertain.
SUMMARY AND RECOMMENDATIONS
●Definition and physiology – The ductus arteriosus (DA) is a fetal vascular connection between the main pulmonary artery and the aorta that normally closes soon after birth (figure 1). A patent ductus arteriosus (PDA) occurs when the ductus fails to completely close after delivery. (See 'Fetal and transitional ductal circulation' above.)
In patients with a PDA, the left-to-right shunting of blood results in an excessive blood flow through the pulmonary circulation and potential hypoperfusion of the systemic circulation, which is dependent on the ratio of pulmonary vascular resistance (PVR) to systemic vascular resistance. The physiologic consequences of this "ductal steal" depend upon the size of the shunt and the response of the heart, lungs, and other organs to the shunt.
●Risk factors – Ductal closure is delayed in preterm infants and the risk of PDA is inversely proportional to gestational age (GA). Respiratory illness and antenatal administration of nonsteroidal antiinflammatory drugs (eg, indomethacin and ibuprofen) are also associated with increased risk of PDA. (See 'Risk factors' above.)
●Clinical features – The following clinical features are seen in the majority of preterm infants with a hemodynamically significant PDA (see 'Findings associated with hemodynamically significant PDA' above):
•Heart murmur – In most infants with a moderate to large PDA shunt, cardiac auscultation demonstrates a heart murmur heard over the entire precordium, but best heard in the left infraclavicular region and upper left sternal border. Immediately after delivery when PVR is high, the murmur initially may be heard only in systole. As PVR falls, the murmur can be heard in systole and diastole, producing the characteristic continuous PDA murmur (movie 1). (See 'Heart murmur' above.)
•Cardiovascular findings indicative of left ventricular overload and pulmonary runoff include prominent left ventricular impulse, bounding pulses, widened pulse pressure, systemic hypotension, and chest radiograph finding of cardiac enlargement.
•Findings of pulmonary overcirculation including tachypnea, apnea, increased carbon dioxide retention, need for respiratory support, and chest radiographic findings of increased pulmonary vascular markings.
•Other findings may include oliguria and metabolic acidosis.
●Diagnosis – The diagnosis of PDA is usually suggested based upon the characteristic clinical findings (eg, heart murmur) and confirmed by echocardiography (movie 2 and movie 3). (See 'Diagnosis' above.)
●Consequences and complications of PDA – Infants with hemodynamically significant PDA have clinical and echocardiographic findings that provide evidence of pulmonary overcirculation (pulmonary edema) and left-to-right shunting, left ventricular overload and systemic undercirculation (eg, oliguria and metabolic acidosis). These infants are at risk for pulmonary edema and hemorrhage, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and episodes of significant hypotension. (See 'Consequences of a PDA' above and 'Associated complications' above.)
