Abstract
One of the more controversial areas currently in neonatal management is the assessment, monitoring, and treatment of the patent ductus arteriosus (PDA). The reasons for this are many and relate to the historical management, significant flaws in the design and execution of previous clinical trials, and subsequently the systematic reviews of management, significant clinical variability in the presentation and pathophysiologic effects of the PDA, relatively poor drug efficacy and risk of side effects, and the emergence of a new group of very low birth weight infants who are relatively well and being managed with less intervention than ever before. These challenges call for a new approach to the management of the PDA. Clinicians need to be able to assess the effect of a PDA and the associated systemic-to-pulmonary shunt in the individual infant rather than taking an all or none treatment approach. This will require the development of better and more usable evaluation tools and an improved understanding of the pathophysiology of PDA not only in the entire population of preterm neonates but also in the individual patient. This chapter will discuss some of these issues and demonstrate the range of pathophysiologic responses of preterm neonates and the potential effects of different treatment approaches, including timing and patient selection options.
Keywords
echocardiography, nonsteroidal anti-inflammatory drugs, patent ductus arteriosus, premature infant
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The simplistic “treat all or treat none” approach to management of a patent ductus arteriosus (PDA) has been increasingly challenged over the past few years as the variation in clinical and hemodynamic presentation has been realized.
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Spontaneous closure rates, poor efficacy of medical treatment, and high open-label treatment rates in clinical trials are among the major factors that have resulted in a lack of confidence in the usefulness of treating a PDA.
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The era of personalized medicine whereby the individual characteristics of the patient (genetics, physiology/pathophysiology, biochemistry, clinical variables) are taken into consideration when deciding on management is ideally suited for many of the neonatal hemodynamic treatment dilemmas, including PDA management.
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Understanding the clinical and hemodynamic variability of an individual patient’s PDA may allow more specific decision-making around when to treat, what to treat, and with what treatment approach. In this regard, better evaluation tools and development of multiparameter scoring systems based on patient characteristics is likely to be increasingly important.
For many years now the default position of most neonatologists has been to treat the patent ductus arteriosus (PDA), particularly in the very low birth weight (VLBW) infant (<1500 g). More recently as our intensive care practices have evolved and the infants for whom we care do better, the need for medical treatment, particularly with the nonsteroidal antiinflammatory drugs (NSAIDs) has been increasingly questioned. The uncertainty has been driven by a number of factors, including our inability to identify infants who would most benefit from treatment, demonstrated high spontaneous closure rates, variable efficacy of the medications available, balancing the risks of side effects, and the failure of trials of treatment in nonspecific subgroups of infants to show clear short- or long-term benefits. However, it is not an all-or-none solution—there are likely to be a subset of newborns with a PDA which should be treated at an appropriate time to avoid possible deleterious effects from a significant left-to-right shunt. Identification of these infants has become a priority, to allow avoidance of side effects and unnecessary treatment. The key to selecting patients for treatment is likely to be understanding the individual pathophysiology (i.e., the effects that the PDA is having in a particular infant). The effects will be dependent on a number of underlying elements—the gestational age of the infant, the volume of any left-to-right shunt (related to the size of the PDA and the pressure difference across it), the effect of steal on the systemic circulation (blood pressure, blood flow to the brain, kidney, and gut), and the effect of pulmonary flooding on the pulmonary circulation (increased respiratory support needs and a subsequent relation to bronchopulmonary dysplasia [BPD] and risks of pulmonary hemorrhage). Clinician-performed ultrasound (CPU) of the heart in the neonatal intensive care unit (NICU), by the physician caring for the baby in a longitudinal setting is set to play an indispensable role in the selection of patients for treatment or no treatment and subsequently the overall management of PDA. Understanding how to assess the underlying elements of the pathophysiologic scenario potentially allows a more individualized decision to be made regarding the need for treatment.
Pathophysiology of Patent Ductus Arteriosus Closure
Understanding the pathophysiologic basis of natural ductus arteriosus (DA) closure is an important aspect of the logical approach to PDA management. Preterm PDA closure is different to term closure, and different clinical situations such as infections, pulmonary vascular resistance and its regulation, and the severity of the underlying lung disease may alter the usual ground rules of PDA closure. The underlying physiology of natural PDA closure is depicted in Fig. 25.1 .
In most term babies, functional closure occurs by 24 hours of age. Intimal ischemia and then necrosis result from the continued intense constriction of the muscular wall and the ductus eventually evolves into the ligamentum arteriosum and is permanently closed. The preterm DA does not follow the same course and is thus less likely to close spontaneously—the more immature the infant, the less the likelihood of early spontaneous closure. The differences in the pathophysiology of closure between term and preterm PDA are outlined in Table 25.1 .
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Issues to be Considered When Deciding Whether to Treat the Patent Ductus Arteriosus
Spontaneous Closure Rates
Modern-day neonatology has come a long way with our vastly improved understanding of developmental cellular physiology, the advent of new technology, and introduction of better treatment modalities. Survival of neonates born greater than 30 weeks’ gestation is almost 100%, and there has been a significant increase in the survival of extremely preterm infants. Due to reduced spontaneous ductal closure rates coupled with significant pulmonary-systemic pressure differences, extremely preterm infants (<28 weeks’ gestation) are at higher risk of complications from the PDA both early on, where there are risks of acute left-to-right shunting with pulmonary flooding and relative reduction of blood flow on the systemic side, and later due to the prolonged effects of left-to-right shunting on the heart, brain, kidneys, intestines, and lungs. A PDA in a relatively mature preterm neonate is of less concern as the left-to-right shunt appears to be tolerated better and the cardiovascular system and cerebral autoregulation protective mechanisms are more developed. Despite this, the systematic meta-analyses regarding PDA treatment include many trials from greater than 20 years ago and trials that focused on larger, more mature infants of up to 33 to 34 weeks of gestation, where spontaneous closure in the first few days is almost inevitable. Inclusion of both extremely preterm neonates and relatively mature neonates in the same study makes it difficult to understand the efficacy of treatment versus the effects of spontaneous closure. The protagonists of no treatment argue on the basis of these studies, despite them including a wide mix of gestational age groups, using poor diagnostic criteria for the PDA, with high rates of open-label treatment in the control group, small sample sizes, and/or often lacking objective criteria at randomization. Importantly, spontaneous closure in the placebo control arm of the randomized controlled trials, as well as high levels of open-label treatment in both trial arms (from 30% to 70%), make the interpretation of outcomes in many of the PDA trials difficult at best. In fact, much of the “efficacy” of our current treatment drugs may be ascribed more to spontaneous closure rates, particularly in more mature infants, rather than the treatment itself. The real natural course of PDA in treatment-naïve extreme preterm neonates and the true efficacy of the medications used for treatment are therefore not well understood.
Recently, several groups have published data about the use of conservative treatment of the PDA. However, to date, these have been descriptive cohort studies only. In a study of the natural evolution of PDA in extremely low birth weight (ELBW) neonates, the authors observed a 73% spontaneous DA closure rate in newborns born less than 28 weeks. However, deaths (both early and late), undiagnosed probable PDAs, and infants discharged home with persistent PDAs were excluded from the study. In the end, 41% of the neonates were excluded from the total sample size of 103, many of whom had morbidity and mortality that could be attributed to the PDA. For instance, causes of death of the excluded babies included pulmonary hemorrhage, severe periventricular/intraventricular hemorrhage (P/IVH), and hypoxic respiratory failure, all of which could be attributed to or at least made worse by a PDA, making the outcome of the study difficult to interpret. It should also be noted here that a high incidence of pulmonary hemorrhage (25% [23/91]) was observed in this study. Similarly in another study, the authors reported a 34% permanent closure rate of PDA in ELBW neonates. However, in this study the authors omitted 26% of the total sample size of preterm neonates because of death or comfort care. The use of x-ray and clinical presentation and not ultrasound to decide on treating the PDA also made these conclusions questionable. However, this study made an important observation and estimated that, for each week of increase in gestational age greater than 23 weeks, the odds of spontaneous closure increase by a ratio of 1.5. There is a direct relationship between gestational age, birth weight, and persistence of the PDA. Narayanan estimated the rate of spontaneous closure is approximately 31% in preterm neonates of 26 to 27 weeks’ gestation during the first 3 to 4 postnatal days, whereas the spontaneous closure rate is approximately 21% at 24 and 25 weeks’ gestation. An Italian study also showed a 24% spontaneous closure rate in 23- to 27-week preterm neonates. The majority of these studies were undertaken in a different era of neonatology than the current, where there is now increasing use of noninvasive ventilation and increasing survival of infants less than 25 weeks’ gestational age. Therefore information about the natural history of PDA in the current day NICU is urgently needed. More recently, two larger observational studies of minimal/no treatment of the PDA have been published from the same group. The first study compares three different PDA management approaches in 138 VLBW infants. Infants received either symptomatic, early targeted (during the first 48 hours), or conservative treatment. The authors found no short-term differences between the groups and a decreased rate of BPD in the conservative treatment group. The second, more contemporaneous study is a retrospective cohort study in two European units which enrolled 297 VLBW infants—280 received conservative PDA management and 85% of PDA closed by hospital discharge with a median time to ductal closure of 71 days in infants of less than 26-weeks’ gestation. Seventeen infants received treatment (13 medical, 4 surgical ligation—overall 10 closed before discharge). The 26 infants who died were not included in the primary analysis, although the authors comment that 16 of the 26 infants had a cause of death potentially related to a PDA. There was no increase in morbidity in the nontreated infants. A significant number of infants were discharged with an open PDA (50 overall or 17%), and by 1 year of age, 30 infants had closed the PDA. Thus the PDA remained open in 20 patients—this is a not insignificant impost on the healthcare system, requiring ongoing follow-up and possibly device-based closure in the future (see Chapter 32 ).
Beside gestation, other factors, which are probably responsible for patency of the DA include histologic chorioamnionitis, neonatal infectious diseases such as sepsis or necrotizing enterocolitis (NEC), neonatal respiratory distress syndrome (RDS) and mechanical ventilation, decreased platelet count within 24 hours after birth, hypoxia, low APGAR scores, and low birth weight.
Consequences of a Patent Ductus Arteriosus
The argument that the PDA is an innocent bystander which may spontaneously close, rather than a condition causing pathology, is becoming more prevalent in neonatology. Waiting for spontaneous closure implies acceptance of any long-term consequences of a PDA, and these consequences are in part related to the timing of intervention. The adverse effects of a PDA are probably related to the amount of time the infant is exposed to a left-to-right shunt.
Physiologically, a PDA can potentially harm a neonate by complications of pulmonary flooding and/or reduced systemic blood flow. Prolonged patency is associated with numerous adverse outcomes, including, prolongation of assisted ventilation and higher rates of BPD, pulmonary hemorrhage, P/IVH, periventricular leukomalacia (PVL), renal impairment, NEC, hypotension, and death. The key issue is whether we can intervene at some point and prevent some or all of these complications, with minimal side effects of the treatment. Importantly, for each individual infant , there will be a different risk/benefit equation.
In most newborn babies, even in the first postnatal hours, the ductal shunt is pure left to right or bidirectional with a dominant left-to-right component, demonstrating that pulmonary pressures are usually subsystemic even shortly after birth. Using superior vena cava (SVC) flow as a surrogate measure of systemic blood flow, we showed a significant negative association between duct diameter and SVC flow at 5 hours of age, but this association was not significant on subsequent studies at 12, 24, and 48 hours. There was a significant association between early low systemic blood flow and development of P/IVH and later NEC, suggesting a possible mechanism by which PDA shunting might play an important role in the pathophysiology of these conditions. There is also mounting evidence to suggest a PDA may cause pulmonary hemorrhage in preterm neonates because of the overload of the pulmonary circulation in the presence of a low pulmonary vasculature resistance and that early ductal treatment may prevent this.
A PDA causes left-to-right shunting of blood, which may flood the lungs and cause pulmonary edema. Pulmonary edema reduces lung compliance, resulting in increased ventilator and oxygen requirements. All these factors together might contribute to the development of BPD. BPD is associated with the persistence of a hemodynamically significant PDA (hsPDA). Each week of a hemodynamically significant DA represented an added risk for BPD (Odds ratio, 1.7). Similarly in another recent study but contrary to the study cited earlier by Letshwiti et al., extreme preterm newborns with PDA who were treated conservatively had a higher incidence of BPD compared with infants without PDA. There is emerging but not unequivocal evidence that a tolerant approach to PDA may be associated with a higher incidence of BPD, particularly if treatment is delayed till after the first postnatal week. Use of multiparameter scoring systems may be predictive of future BPD and death—a high PDA severity score on day 2 was associated with these outcomes.
A PDA may cause hemodynamic alterations, resulting in “steal” of blood from the systemic circulation, including the mesenteric arteries, with the consequences of decreased oxygen delivery to the gut and with the potential of tissue injury and NEC. Even a small PDA can reduce mesenteric artery flow and decrease the expected postprandial increase in blood flow. Because reduced intestinal blood flow is a contributor to the development of NEC, PDA may be a causative factor for NEC. In a study involving a relatively large number of neonates, PDA was an independent risk factor for the development of NEC in VLBW infants.
There is ample evidence on the basis of Doppler and near-infrared spectroscopy (NIRS) studies to suggest that cerebral blood flow is reduced in the presence of a PDA. In a based study using NIRS, cerebral tissue oxygen saturation was lowest in the group of newborns just prior to the surgical closure of PDA after a failed trial of medical treatment (indomethacin). The magnetic resonance imaging (MRI)-measured global and regional brain volume showed a trend toward lower volumes in the group that had met criteria for surgical ligation compared with the groups which were treated medically and did not have a PDA. The surgical group also had a statistically significant lower cerebellar volume compared with other groups. The authors attributed this observation to the prolonged exposure to left-to-right shunting because of the amount of time elapsed between the diagnosis of PDA and actual surgical closure. PDA has an effect on cerebral hemodynamics, but whether it is causative for P/IVH in a small number of infants is a question which remains unanswered. Cerebral autoregulation is likely to play some role, particularly in immature infants, in protecting against P/IVH (see also Chapter 6 ). Intact autoregulation is variable in immature infants (see also Chapter 2 ), and one of the risk factors for impaired autoregulation may be a PDA resulting in a period of reduced cerebral blood flow that might impair the autoregulatory mechanism. Early treatment with indomethacin may result in both closure of the PDA and protection against P/IVH, and this is one area where the evidence is strong. However, many clinicians are not convinced that early prophylactic treatment of the PDA is helpful, because of the lack of demonstration of improved neurodevelopmental outcomes in infants treated early with indomethacin, PDA is also a risk factor for development of PVL. Last but not the least, PDA is associated with a higher rate of mortality in preterm neonates. In a retrospective study, after adjustment for perinatal factors, level of maturity, disease severity, and morbid pathologies, the hazard risk for death in neonates with a PDA was eightfold higher than in those with a closed ductus. Exclusion of patients who died during the first 2 weeks or inclusion of those who underwent ductal ligation did not change the findings. In neonates born prior to 28 weeks of gestation, a PDA diameter ≥1.5 mm on postnatal day 3 was associated with greater odds of mortality.
One of the aims of contemporary PDA management could be to identify and target a population which would be most likely to benefit from PDA treatment. To achieve this aim we need to address three key questions:
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When to treat a PDA?
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Which PDA to treat?
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How to treat a PDA?
When to Treat?
The time frame of treatment determines some of the likely outcomes. P/IVH and pulmonary hemorrhage are early complications of a PDA, usually developing during the first 3 to 7 days of postnatal life. There is reasonably good evidence that early treatment of the PDA (mainly with indomethacin) can prevent both P/IVH and pulmonary hemorrhage, but to achieve this, treatment needs to have been given prior to entering the risk period (days 2 to 7) for these complications. Of note is that indomethacin, unlike ibuprofen, decreases cerebral blood flow and improves cerebral blood flow autoregulation at least in part independently of its inhibitory effect on prostaglandin synthesis. Therefore the effect of prophylactic indomethacin on decreasing the rate of P/IVH or white matter injury is not only related to the drug-induced decrease/cessation of ductal shunting. Assessing whether PDA treatment can prevent later complications such as NEC or BPD, which have a multifactorial etiology and a longer development phase, is more difficult. There are some animal data to support prevention of BPD by early ductal closure. In a baboon model, surgical ligation on day 6 had no effect on lung histology; conversely, early indomethacin treatment improved pulmonary mechanics and minimized lung injury by limiting pulmonary blood flow. Demonstrating this in the human infant is more difficult partly due to the multifactorial etiology but also because in most clinical trials there is no true placebo group. High open-label rates of treatment meant that many infants enrolled in PDA treatment trials still received NSAIDs—just at a later time point. Therefore the natural history of an untreated PDA in a clinical trial setting is relatively unknown.
Clinical symptoms of an hsPDA such as a murmur, active precordium, high volume pulses, poor growth, and increased work of breathing are nonspecific and might develop later in the clinical course. Signs of cardiac failure usually do not develop until the second or third postnatal week. Most PDA-related Randomized control trials (RCTs) were not designed to address the question of whether or not a symptomatic PDA should be treated during the neonatal period; they were designed instead to assess the relationship between timing of treatment and efficiency of PDA closure. By the time the DA declares itself, it may already be too late and it may have already contributed to the development of one of the complications of prematurity. Symptomatic treatment trials are scarce, and results did not show any major advantage in terms of prevention of adverse effects from the PDA. Studies from the presurfactant and antenatal steroid era suggest early symptomatic treatment may reduce the duration of mechanical ventilation and BPD compared with late symptomatic treatment.
The efficacy of NSAIDs commonly used for the treatment of PDA decreases with increasing postnatal age as the balance of vasodilators changes from a system regulated predominantly by prostaglandins to one regulated by other vasodilators. Up to 85% of PDAs would close if the first dose of indomethacin was administered within 24 hours after birth, and the rate decreases to 48% if it were started 72 hours or more after birth. So not only does early treatment potentially allow treatment in a period before significant complications appear, it will also increase the likelihood of successful closure. Another benefit of earlier treatment is fewer potential side effects—particularly gut-associated side effects such as spontaneous intestinal perforation (SIP) and NEC. In the early prophylactic treatment studies, there is no increased rate of gut-associated side effects.
The value of early asymptomatic treatment is uncertain. A Cochrane analysis consisting of three small RCTs concluded that asymptomatic treatment might be associated with fewer subsequent PDAs, and there was a reduction in duration of supplemental oxygen. There were no reported long-term outcomes in the included trials. It should also be noted here that the population included in the trials were a mixed population and included neonates up to 1700 g. Another trial subsequent to this Cochrane review using ibuprofen did not show any difference in terms of clinical outcome but showed a trend toward decreased PVL at 36 weeks’ postmenstrual age. One of the issues with asymptomatic treatment is that it exposes a lot of infants to the adverse effects of medical treatment, some of whom would probably not have required treatment and would have undergone spontaneous closure.
Prophylactic Treatment
It is clearly not known how long the DA can be left open without causing potential harmful effects. Prophylactic treatment, which is usually instituted within the first 24 hours after birth, is most widely studied and probably the most effective mode of PDA treatment. The Cochrane analysis that includes 19 trials comprising 2872 infants concluded that prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic PDA, the need for duct ligation, and decreased rate of P/IVH, particularly severe P/IVH. There was also a borderline decrease in PVL, ventriculomegaly, and other white matter abnormalities. The Cochrane analysis concluded that there is a statistically nonsignificant trend toward a decrease in pulmonary hemorrhage. It should be noted here that out of the four trials which were included for the analysis, three trials showed a significant decrease in the incidence. However, the large Trial of Indomethacin Prophylaxis in Preterm infants (TIPP) did not show a statistically significant protection against pulmonary hemorrhage in the primary analysis, and with this trial added to the meta-analysis there was no benefit for pulmonary hemorrhage reduction overall.
It is noteworthy that on reanalysis of the TIPP trial, prophylactic indomethacin reduced the rate of early serious pulmonary hemorrhage, mainly through its action on PDA. There was an overall reduction of pulmonary hemorrhage by 35%, and a reduced risk for PDA explained 80% of the beneficial effect of prophylactic indomethacin on serious pulmonary bleeds. Similarly in a relatively recent double-blinded RCT, early cardiac ultrasound-targeted treatment of a large PDA resulted in a significant reduction in early pulmonary hemorrhage.
Although prophylactic indomethacin has been shown to decrease severe forms of P/IVH, the long-term effect on neurodevelopmental outcomes is equivocal and somewhat improved. The relevance of the long-term versus short-term outcomes debate regarding its value will continue. Neil Marlow in his scientific philosophy paper asked a very pertinent question—“Is the primary outcome (mortality and severe neuro disability) directly causally relevant to the intervention under study?” He argues death can be from a less prevalent factor, which is not adjusted for, and considers neurodevelopment and death as complex outcomes. We should not be afraid to regard 2-year outcomes as proof of safety rather than efficacy and therefore be reassured in using the treatment. Certainly there is enough evidence to suggest that indomethacin does not adversely affect neurodevelopmental outcome. Very few RCTs have compared neurodevelopmental outcome and death in the follow-up. Only one RCT, which has followed neonates up to school age, did not find any beneficial effect of indomethacin. The TIPP trial’s 18-month follow-up did not show any major difference between indomethacin and the control group in terms of severe neurodevelopmental outcome and death; however, controversy exists regarding the study design and the interpretation of these results. The argument pertains to inadequate sample size, later indomethacin exposure of the controls, and the low incidence of P/IVH, making it difficult to come to any meaningful conclusion about neurodevelopmental outcome despite this being by far the largest trial of this intervention. It has been suggested that the 18-month follow-up performed in TIPP, as in many other long-term follow-up studies, may have failed to detect subtle neurodevelopmental abnormalities that became evident later in childhood. A recent population-based cohort study reported that treatment for PDA may be associated with a greater risk of adverse neurodevelopmental outcome at age 2 to 3 years. However, in the analysis, the treatment group was more likely to have a lower birth weight, head circumference, gestational age, and APGAR scores. The treatment group was also more likely to undergo mechanical ventilation for a longer period with more comorbidity, including BPD, retinopathy of prematurity (ROP), and infection. This gives the impression that patients in the treatment group were generally sicker than those in the control group, highlighting one of the drawbacks of retrospective analysis of data. In addition, in the multivariate analysis for neurodevelopmental outcome, no adjustment was made for P/IVH and NEC. It has been shown that there is a decrease in cerebral blood flow with increasing left-to-right shunt through a PDA, that indomethacin improves regional cerebral oxygenation in hsPDA, and that prolonged indomethacin exposure was the only variable independently associated with a lower risk of white matter injury or brain abnormality. Males who received prophylactic indomethacin had significantly higher verbal scores when compared with control males. Ment and colleagues described trends favoring the prophylactic indomethacin group in cognitive functioning, some of which became statistically significant with adjustment for certain baseline variables. Therefore the question as to what effect prophylactic indomethacin has on neurodevelopment is still not answered.
There is little evidence to support or refute the role of a PDA in NEC. The only study showing a decreased incidence of NEC was an older, unique study in infants less than 1000 g after early prophylactic PDA ligation. Studies have consistently shown a reduction in intestinal blood flow in the presence of a PDA, providing some plausibility for an association with gut injury and NEC. Mesenteric artery flow decreases despite an increase in left ventricular output (LVO). Superior mesenteric artery flow usually increases after feeding; however, this physiologic phenomenon is blunted in the presence of a PDA. In another human study, higher rates of NEC and feeding intolerance were seen in infants with a large PDA. Therefore we suspect PDA might play a role in the pathophysiology of NEC, and treatment may be able to reduce this complication. However, due to the decreasing incidence of NEC in many nurseries a very large trial would be required to prove causation.
From the previous discussion, it is clear that prophylactic treatment definitely gives short-term benefit against severe P/IVH and pulmonary hemorrhage. The treatment also reduces the incidence of symptomatic PDA and need for surgical ligation. Despite the clear short-term benefits, this has not translated into improved outcomes for surviving infants. Early prophylactic treatment may improve neurodevelopmental outcome, although available evidence has not conclusively supported this notion.
Although a “prophylactic” treatment approach has several important benefits, it also results in overtreatment of a PDA that would have closed spontaneously. As per the previous discussion, it is probable that at least 30% of the PDAs in extremely premature newborns close spontaneously, and it is important to identify these patients to avoid unnecessary exposure to medications. If prophylactic treatment is desired, indomethacin is currently the drug of choice because ibuprofen has not as yet been shown to have similar short-term benefits. On the other side, there is little evidence to suggest that treating PDA when it becomes symptomatic is helpful in the long term, rather we may lose an opportunity to prevent significant early complications.
The Cochrane analysis that includes 19 trials comprising of 2872 infants showed a safe profile of prophylactic indomethacin. Increased serum creatinine, NEC, spontaneous perforation, thrombocytopenia, ROP, and excessive bleeding were not of concern. Oliguria and hyperbilirubinemia are short-term and reversible side effects. Indomethacin treatment for PDA does not increase NEC risk and, in fact, may decrease the risk. Indomethacin treatment is associated with an increased risk of intestinal perforation, especially when given after the first 24 hours or combined with systemic glucocorticoids. Very early prophylactic treatment is feasible even in infants born at 23 to 24 weeks’ gestation without any side effects of the drug. However, these patients might be at risk for SIP if they are given systemic steroids during the first few days after indomethacin has been started.
If early prophylactic treatment could be targeted at only those with evidence of poor PDA constriction, then the benefits may be maximized and potential harms decreased. Identification and targeting of a particular subset of the population who are least likely to undergo closure of their PDA and are most vulnerable to complications are therefore priorities. Cardiac ultrasound is an obvious way to aid in identifying this subgroup of patients and it is in this area that the efforts of the author’s group have been focused.
Different timings of interventions along with their advantages and disadvantages from a pathophysiologic viewpoint are shown in Fig. 25.2 , with pros and cons listed in Table 25.2 . A schematic representation of the relationship between various complications of prematurity, the postnatal age at which they commonly occur, and various treatment approaches is provided in Fig. 25.3 .
| Treatment Type | Advantages | Disadvantages |
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| Prophylactic (within 6–24 h of life, preferably within the first 12 h) | Most widely studied Some benefits (decreased IVH, pulmonary hemorrhage) |
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| Early asymptomatic (usually by day 3–7 on the basis of ultrasound/clinical signs) | Exposes fewer babies to the risks of treatment |
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| Symptomatic (usually after postnatal day 3–4) | Exposes fewest babies to the risks of treatment |
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| Conservative (no medication or surgery) | No initial exposure to medication but risk of need for later treatment |
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