Patent ductus arteriosus (PDA) in preterm infants: Clinical features and diagnosis

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) (figure 2) 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 (PDA) in preterm infants: Management and outcome" and "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) 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 1 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 during fetal development — The fetal ductus arteriosus has a diameter similar to that of the descending aorta (figure 1) [2]. Key factors that maintain ductal patency in the fetus include:

●Low arterial oxygen content

●Endogenous vasodilators, including prostaglandins and nitric oxide

The role of prostaglandins in maintaining ductal patency provides the rationale for the use of inhibitors of prostaglandin synthesis (eg, indomethacin, ibuprofen, and acetaminophen [paracetamol]) in the treatment of PDA. (See "Patent ductus arteriosus (PDA) in preterm infants: Management and outcome", section on 'Pharmacologic therapy'.)

Maternal use of nonsteroidal anti-inflammatory drugs (NSAIDs, eg, indomethacin, ibuprofen) for a prolonged period after 30 weeks gestation also can induce intrauterine ductal constriction [3,4]. Use of NSAIDs during pregnancy is discussed separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs' and "Inhibition of acute preterm labor", section on 'Cyclooxygenase inhibitors (eg, indomethacin)'.)

Spontaneous ductal closure after birth — 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 [5]. The predominance of constricting agents results in ductal constriction. (See "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults", section on 'Ductal constriction'.)

The initial sustained constriction of the ductus is the first step in permanent anatomic closure. Closure begins 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 usually within the first 12 to 24 hours of birth. Permanent closure is usually completed by two to three weeks of age. (See "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults", section on 'Ductal constriction'.)

●Preterm infants – In preterm infants, ductal constriction and permanent closure are delayed; the risk of PDA increases with decreasing 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) [7-10].

The natural history of spontaneous ductal closure in extremely preterm infants was described in a study of 214 infants who were managed conservatively [11]. Overall, 91 percent had spontaneous closure at time of last follow-up (median follow-up six months). Spontaneous closure occurred prior to discharge from the neonatal intensive care unit (NICU) in 70 percent of patients at a median of 36 weeks corrected gestational age (CGA). Of the 64 infants who continued to have PDA at time of NICU discharge, 69 percent subsequently had spontaneous closure at a median of 53 weeks CGA. Of the 20 patients who continued to have PDA at last follow-up, all were noted to have small clinically insignificant PDAs.

Complete anatomic closure may take up to several months in preterm neonates. 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 [7,12]. 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 [8,13-15].

Reopening of the ductus — In term infants, ductal constriction is followed rapidly by histologic changes that generally prevent subsequent reopening. However, in preterm infants, the ductus can reopen after closure (either spontaneous closure or closure induced by medical treatment) [16,17]. Ductal reopening is likely influenced by the same prematurity-related factors that blunt the ductal constriction immediately after birth. 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 [18]. Ductal reopening occurred more frequently in infants <27 weeks GA compared with more mature infants.

CONSEQUENCES OF A PDA — Blood flow through a PDA results in a left-to-right shunting from the aorta into the pulmonary arteries. This leads to increased flow through the pulmonary circulation (pulmonary overcirculation) and potentially to hypoperfusion of the systemic circulation (systemic undercirculation). The physiologic consequences of this "ductal steal" depend upon the size of the shunt and the compensatory response of the heart, lungs, and other organs. It should be noted that shunting through the ductus arteriosus is normal during fetal development (although in the fetus, the direction of ductal flow is right-to-left). Ductal shunting can also play an important role during the transition at birth. For example, in newborns with persistent pulmonary hypertension, the ductus relieves excess stress on the right ventricle by shunting blood right-to-left from the pulmonary artery to the aorta. In newborns with ductal-dependent congenital heart disease, the ductus is vital for supporting the circulation. However, in preterm neonates without these conditions, PDAs can have deleterious effects when there is excessive left-to-right shunting.

Potential adverse consequences associated with hemodynamically significant PDAs include the effects of pulmonary overcirculation (pulmonary edema, hemorrhage, bronchopulmonary dysplasia [BPD], and pulmonary hypertension [PH]) and the effects of systemic undercirculation (hypotension, necrotizing enterocolitis [NEC], intraventricular hemorrhage [IVH], and acute kidney injury [AKI]).

●Effects of pulmonary overcirculation – In preterm infants, a symptomatic PDA is associated with increased risk of pulmonary edema, pulmonary hemorrhage, BPD, and PH. (See 'Hemodynamically significant PDA' below.)

•Pulmonary edema — Increased pulmonary blood flow from left-to-right shunting across a large PDA can cause pulmonary edema (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) [19]. Ductal diameter measured at five hours of age also was greater in the infants who subsequently developed pulmonary hemorrhage.

•BPD — A hemodynamically significant PDA is associated with increased risk of developing BPD [20-22]. In a study of 865 very low birth weight (VLBW) infants (BW <1500 g) who survived to 36 weeks postmenstrual age, patients who were diagnosed with PDA in the first week after birth had a 4.5-fold increased risk of BPD compared with those who did not have PDAs [22].

The risk of BPD and other long-term pulmonary sequelae may be related to the interplay between the duration of ductal patency and need for mechanical ventilation [23-25]. In a study of 423 infants <27 weeks gestation, an associated between moderate-to-large PDA and risk of BPD was only detected if the PDA had been present for ≥7 days [24]. In another study, moderate-to-large PDAs were associated with increased risk of BPD only among infants requiring ≥10 days of mechanical ventilation [25]. Thus, it appears that prolonged exposure to both a PDA and mechanical ventilation may be required for development of BPD. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis".)

•Pulmonary hypertension – PH is an important contributor to morbidity and mortality in preterm infants with BPD. Patients with BPD who have prolonged exposure to moderate-to large PDA are at increased risk for developing PH [26]. (See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)

●Effects of systemic undercirculation – Although preterm infants with a PDA typically have compensatory increased cardiac output, the postductal blood flow may be reduced because if there is a large left-to-right shunt. 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.

•Hypotension — Moderate or large PDAs can be associated with clinically significant hypotension requiring vasoactive therapy [27-29]. In some cases, hypotension can persist even after surgical ligation of the PDA and it may be refractory to vasopressor therapy. This may be due to low cortisol levels, impaired ventricular function, and/or abnormal vascular tone [30,31]. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation" and "Neonatal shock: Management".)

•Intraventricular hemorrhage — Moderate or large left-to-right shunts appear to be associated with increased risk of IVH, most likely due to the hemodynamic instability that can occur neonates with large PDAs [32]. Infants with significant PDAs also have reduced cerebral blood flow and oxygenation, but data are lacking demonstrating an association of these findings with IVH [33,34]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'Risk factors other than GA'.)

•Necrotizing enterocolitis — It is thought that decreased blood flow to the abdominal aorta from ductal steal through large PDAs may contribute to increased risk of NEC in preterm neonates. However, data are lacking to conclusively demonstrate that the circulatory instability associated with PDA contributes to risk of NEC. (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Circulatory instability'.)

•Acute kidney injury – Neonates with large PDAs are at increased risk of AKI [35,36]. In a secondary analysis of the AWAKEN cohort study that included 526 VLBW infants, the incidence of AKI was nearly two-fold higher in infants with versus without PDA (55 versus 24 percent, respectively) [36]. In this study, PDA management strategy (conservative management versus pharmacologic treatment versus surgical or transcatheter intervention) did not appear to influence the likelihood of AKI. Other studies have demonstrated that medical therapy with nonselective cyclooxygenase (COX) inhibitors, particularly indomethacin, is associated with increased risk of AKI. (See "Patent ductus arteriosus (PDA) in preterm infants: Management and outcome", section on 'Adverse effects'.)

RISK FACTORS — The risk of PDA increases with decreasing gestational age (GA) and birth weight (BW), and chromosomal abnormalities [37-41]. In very low birth weight (VLBW) infants (BW <1500 g), the incidence of PDA is approximately 30 percent [42]. For healthy infants greater than 30 weeks gestation, the ductus typically closes by the fourth day of life [43]. 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 [16,44]. 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 [16,45,46].

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 [47-49]. 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 [50,51]. 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 (table 1):

●Signs of increased pulmonary circulation, including tachypnea, apnea, and/or increased requirements for respiratory support including mechanical ventilation. Chest radiography typically demonstrates increased pulmonary vascular markings and/or edema (image 1). (See 'Radiographic and laboratory findings' below.)

●Signs of left ventricular overload include prominent left ventricular impulse and cardiomegaly on chest radiograph (image 1).

●Systemic circulatory findings include bounding pulses and a widened pulse pressure (>25 mmHg difference between diastolic and systolic blood pressure [BP] or diastolic BP <50 percent of the systolic BP). Diastolic BP is typically low in patients with hemodynamically significant PDAs.

●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. (See 'Differential diagnosis' below.)

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) [52]

●Necrotizing enterocolitis (NEC) [53]

●Heart failure

●Intraventricular hemorrhage (IVH) [54]

●Prolonged need for ventilator and/or oxygen support

●Acute kidney injury [35,36]

Radiographic and laboratory findings

●Chest radiograph – In patients with large PDAs, the chest radiograph typically shows cardiac enlargement and increased pulmonary vascular markings (image 1). However, these findings are nonspecific and can be seen in other causes of neonatal heart failure (eg, congenital heart disease [CHD]).

●B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) – Patients with large PDAs often have elevated BNP or NT-proBNP levels indicating increased filling pressures in the heart [55-58]. However, clear reference ranges and cut-off values have not been established in the preterm neonatal population and the diagnostic accuracy of these tests vary depending on the assay used and the population studied [59]. Elevated BNP or NT-proBNP is not a specific finding of PDA since it can also be seen in neonates with CHD or severe respiratory disease.

The role of monitoring BNP or NT-proBNP in neonates with large PDAs (eg, to assess for spontaneous closure and/or determine the need for treatment) is unclear and requires further study. In our center, we do not use BNP or NT-proBNP levels for this purpose.

●Electrocardiogram (ECG) – The ECG is not helpful in the diagnosis of PDA in preterm infants.

DIAGNOSIS — The diagnosis of PDA is usually suspected by its characteristic clinical findings (murmur, widened pulse pressure, signs of pulmonary congestion) (table 1) and is confirmed by echocardiography.

Echocardiogram — Echocardiogram is performed to confirm the presence of a clinically significant PDA. 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) [60].

We do not routinely perform echocardiography in preterm infants without a murmur or other clinical findings suggestive of PDA unless there is an unexplained deterioration in respiratory status, which may raise clinical suspicion for a "silent" PDA. (See 'Clinical features' above and 'No role for routine screening' below.)

Hemodynamically significant PDA — It is important to distinguish between a hemodynamically significant PDA versus a trivial or mild (small) PDA. PDAs that are not hemodynamically significant do not require intervention. The need for intervention in patients with hemodynamically significant PDAs depends on the severity and persistence of the findings, as discussed separately. (See "Patent ductus arteriosus (PDA) in preterm infants: Management and outcome", section on 'Our approach'.)

In our practice, we define "hemodynamically significant" using both clinical findings and echocardiographic measurements [41,61]. The assessment is based upon multiple findings rather than a single isolated finding.

●Clinical findings that indicate a clinically significant PDA include (table 1) (see 'Findings associated with hemodynamically significant PDA' above):

•Need for substantial respiratory support (mean airway pressure ≥8 cm H2O and/or fraction of inspired oxygen [FiO2] >0.4)

•Evidence of hypoperfusion (oliguria, acidosis, need for vasoactive medication to treat hypotension) that are not otherwise explained

•Physical findings of wide pulse pressure (>25 mmHg difference between diastolic and systolic blood pressure [BP] or diastolic BP <50 percent of the systolic BP) or pulmonary rales

•Cardiomegaly on chest radiograph (image 1)

●Echocardiographic findings that indicate a hemodynamically significant include (table 2) [41,62,63]:

•PDA diameter >1.5 mm [41,62,64-66]. However, the PDA diameter may need to be adjusted for size of the patient especially in the smallest infants. This can be done by correcting the measurement for the infant's body surface area or in relation with the diameter of left pulmonary artery (LPA) [62,63]. A PDA:LPA diameter ratio of ≥1 indicates a large PDA and a ratio of ≥0.5 to <1 indicates a moderate PDA [67,68].

•Diastolic flow reversal in the abdominal aorta. This finding is a highly sensitive marker of a clinically significant PDA [62,63].

•Flow velocity ≤2.5 m/sec across the PDA or mean pressure gradient of ≤8 mmHg across the PDA. This finding indicates unrestricted flow consistent with a large PDA.

•Left atrial or left ventricular chamber enlargement

NO ROLE FOR ROUTINE 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, we suggest against routine screening. We perform echocardiography selectively only if there are clinical signs of a hemodynamically significant PDA. (See 'Diagnosis' above.)

The impact of universal screening was investigated in a study of 1513 EPT infants from the EPIPAGE 2 cohort, a prospective population-based study conducted in France [69]. 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 0.54-0.98) and a lower incidence of pulmonary hemorrhage (5.6 versus 8.9 percent; OR 0.60, 95% CI 0.38-0.95). The higher mortality in the non-screened group was primarily observed in untreated infants; however, it is unclear how many of these patients had PDAs. 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 [70]. 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. The notion that early diagnosis and treatment of PDA improve outcomes is contradicted by multiple randomized trials comparing early treatment with expectant management of PDA. These trials have generally demonstrated that while early treatment results in earlier closure of the PDA, other clinical outcomes (mortality, bronchopulmonary dysplasia [BPD], necrotizing enterocolitis [NEC], NDI) are generally similar between the two approaches [71]. These data are discussed in detail separately. (See "Patent ductus arteriosus (PDA) in preterm infants: Management and outcome", section on 'Comparison of approaches'.)

The findings of the EPIPAGE 2 study 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.

DIFFERENTIAL DIAGNOSIS — Other diagnoses associated with continuous murmurs include systemic arteriovenous malformations, fistula, and aortic-pulmonary window. These are far less common than PDA. Occasionally, combined aortic stenosis and regurgitation or 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 can be distinguished from these conditions with echocardiography. (See "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) in term infants, children, and adults", section on 'Differential diagnosis'.)

SUMMARY AND RECOMMENDATIONS

●Definition and physiology – The ductus arteriosus (DA) is a fetal vascular connection between the main pulmonary artery and the aorta (figure 1) that normally closes soon after birth. A patent ductus arteriosus (PDA) (figure 2)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. 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). Closure is also less likely to occur in infants who have neonatal respiratory distress syndrome and who did not receive antenatal corticosteroids. (See 'Risk factors' above.)

●Clinical features – The following clinical features are seen in most preterm infants with a hemodynamically significant PDA (table 1) (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 diastolic runoff include prominent left ventricular impulse, bounding pulses, widened pulse pressure, systemic hypotension, and cardiomegaly on chest radiograph (image 1).

•Findings of pulmonary overcirculation include tachypnea, apnea, need for substantial respiratory support, and evidence of pulmonary edema on chest radiograph (image 1).

•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, widened pulse pressure, signs of pulmonary congestion (table 1)) 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 indicate significant left-to-right shunting, including evidence of pulmonary overcirculation (pulmonary edema, high respiratory support requirements) and evidence of systemic undercirculation (eg, oliguria, metabolic acidosis). Infants with these findings are at risk for adverse consequences of PDA including pulmonary hemorrhage, bronchopulmonary dysplasia, pulmonary hypertension, necrotizing enterocolitis, intraventricular hemorrhage, and acute kidney injury. (See 'Consequences of a PDA' above and 'Associated complications' above.)