Prematurity and Congenital Heart Disease: Review and Future Directions

The evaluation and management of fetuses and neonates with congenital heart disease (CHD) is inherently challenging. In this patient population, the typical multisystem problems affecting preterm infants are amplified. Similarly, the physiological and developmental problems with myocardial structure and function that exist in all newborns are even more problematic in those born prematurely with CHD.

In this review, the authors provide an overview of the epidemiology of preterm infants with CHD, discuss recent data that inform complex decision-making on issues related to the timing of delivery, provide an updated preoperative evaluation and management recommendations, They summarize the current approach to cardiac surgical timing and options, review recent outcomes data, and describe gaps in the literature that require additional investigation.

Congenital heart disease (CHD) is the most frequently reported birth defect (6 to 10 per 1,000 live births) in newborns and is associated with a more than twofold increase in the risk of preterm birth (PP), defined as birth before of 37 completed weeks of gestation. (1)(2)(3)(4)(5)(6)(7)

Population-based studies attribute this PP risk largely to spontaneous preterm birth, rather than medically induced labor or cesarean delivery. (8)(9) Premature rupture of membranes before labor accounts for more than 50% of these cases, with additional cases related to extracardiac/genetic abnormalities and environmental factors. (9)

Although most babies with CHD are born full-term between 37 and 41 weeks of gestation, the highest incidence of CHD is seen in very low birth weight (VLBW) infants (<1500 g) born between 25 and 32 weeks. gestational age (GA) (up to 116 per 1000 live births). (10) Relative to full-term newborns, birth in this GA range is associated with a 5-fold higher incidence of CHD (i.e., defects that would be expected to warrant surgery or medical therapies during infancy). (10) (11) (12) (13)

CHD is suspected to play a causal role in PP (e.g., fetal heart failure causing polyhydramnios) and intrauterine growth restriction (e.g., fetal hypoperfusion causing growth restriction). (12)

The 2011 Vermont Oxford Network database study of 99,786 VLBW infants born or treated in 703 ICUs found that 42% of VLBW infants with serious CHD (defined as injuries requiring cardiac surgery or cardiac catheterization interventions). the first year after birth) were born small for gestational age, compared to 21% of those without, and with a higher frequency of heart disease lesions associated with extracardiac malformations. (12)

The EPICARD population-based cohort study demonstrated a higher risk of PP in cases of CHD associated with extracardiac and syndromic patterns than with isolated CHD. (9)

The most common cardiac malformations associated with prematurity are tetralogy of Fallot (18.6% of CHDs requiring cardiac surgery or catheterization within the first year of age), aortic coarctation (11.5%), complete atrioventricular canal (9.1 %), pulmonary atresia (8.2%) and double outlet right ventricle (7.6%). (9)(12)(13)(14) These data differ from studies of live births in general in which tetralogy of Fallot and aortic coarctation are among the 5 most common complex heart defects; however, complete atrioventricular canal, pulmonary atresia, and double outlet right ventricle are relatively less common. (12)

Maternal factors may also play a role in the relationship between CHD and PP, with complications such as viral infections (eg, rubella) and maternal diabetes having an increased risk of CHD and polyhydramnios, which may lead to PP. (15)(16)(17)

Only 20% of congenital heart disease (CHD) cases would be identified prenatally if fetal heart screening were limited to established high-risk groups, such as those with a family history of CHD and exposure to teratogens. (11) Fetal findings of concern for CHD include extracardiac anomalies (e.g., omphalocele, duodenal atresia, spina bifida, vertebral anomalies, extremity anomalies), arrhythmia, hydrops, abnormal obstetric ultrasound, and increased nuchal translucency. .

Maternal findings that raise concern for CHD include a history of CHD, exposure to teratogens (eg, lithium, antiepileptic drugs, cocaine), metabolic disorders (eg, diabetes), and phenylketonuria. These findings should require fetal echocardiography and advice on early prenatal genetic testing, when indicated. (18) Postnatal echocardiography is also necessary for definitive evaluation of CHD in some neonates with the aforementioned risk factors and with clinical concern for cardiac defects.

Other prenatal considerations include evaluation of the fetal environment. Recent population-based data identified that the fetal environment was affected in 25% of neonates with complex CHD. (19) Of the multiple factors contributing to an impaired fetal environment, impaired fetal growth (identified postnatally as babies born small for gestational age) was identified as the primary driver of mortality in this population. (19)

Maternal placental syndrome was identified as the other major factor contributing to an impaired fetal environment and, when associated with impaired fetal growth, did not have a significant impact on mortality risk. (19) Thus, the proposed mechanism for growth impairment in this population remains unclear, but it has been postulated that inadequate fetal cardiac output (CO) may play a role. (twenty)

In the past, it was common for fetuses with critical CHD to have a scheduled delivery between 37 and 38 weeks of gestation, with the intention of facilitating postnatal care in a congenital heart center. However, recent literature has consistently shown that delivery of neonates with CHD in the “early term” period between 37 and 38 weeks of gestation is associated with increased in-hospital morbidity and mortality . (13)(21)(22) These data are consistent with larger population-based studies that included newborns without CHD or other congenital defects, which have also found that delivery before 39 weeks of gestation is associated with worse outcomes for both short and medium term. (23)

Given these findings, elective delivery before 39 weeks of gestation is not recommended for fetuses with CHD unless there are placental complications, maternal conditions, specific concerns about the well-being of the fetus, or logistical issues related to intrapartum care or immediate postnatal intervention. (18)

The American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine, and the Eunice Kennedy Shriver National Institute of Maternal-Fetal Medicine have published separate guidelines and consensus opinions related to medically indicated late preterm births (34 0/ 7–36 6/7 weeks) and premature births (37 0/7–38 6/7 weeks). (24)(25)

Placental/uterine conditions , fetal growth restriction, multiple gestations, maternal hypertensive disorders including preeclampsia, pregestational or poorly controlled gestational diabetes, and premature rupture of membranes are examples of medical indications for delivery before 39 weeks of gestation. . (24) However, published recommendations are based on limited data and decisions about timing of delivery are complex and must take into account maternal and neonatal risks, accuracy of pregnancy dating, practice setting, and preferences. from the patients. For these reasons, decisions about the timing of delivery must be individualized to the needs of the expectant mother and her fetus. Multidisciplinary planning with close communication between the obstetrics, neonatology and cardiology teams is essential.

The transition from placental support of the fetal circulation to neonatal support of the circulation represents an extreme physiological change that may have deleterious effects on a newborn with CHD, and this risk must be weighed when considering early delivery. Fetal circulation almost always allows cardiac bypass to redistribute blood flow and maintain adequate levels of CO and oxygenation, despite the presence of CHD; therefore, most CCs are well tolerated before birth. (26)

After delivery, certain cardiac injuries require patency of the fetal shunts for systemic or pulmonary blood flow, infusion of prostaglandin E1 (PGE1) to prevent closure of the patent ductus arteriosus, and/or invasive cardiac interventions for further stabilization of the circulation. For example, fetuses with left cardiac hypoplasia syndrome (LSHS) or dextrotransposition of the great arteries (d-TGA) who have a severely restrictive foramen ovale may require emergent opening of the atrial septum by catheterization after birth. Lower GA and lower birth weight increase the technical difficulty, risks, and morbidity associated with such invasive cardiac procedures, providing further reason to avoid preterm births when possible. (27)

Despite the risks associated with preterm or early-term birth, fetal compromise may justify preterm delivery, especially if there is an opportunity to provide effective therapeutic intervention in the extrauterine setting. One such condition is the development of non-immune hydrops fetalis (NIHF). Considered an ominous prenatal sign, NIHF is defined as 2 abnormal fluid accumulations in the fetus, such as ascites, pleural or pericardial effusions, and skin edema, that are not caused by red blood cell alloimmunization. (28)

Although HFNI has a wide range of causes, cardiovascular abnormalities are the most common and include structural heart problems (specifically right heart defects), arrhythmias, cardiomyopathies, cardiac tumors, or vascular abnormalities. (28) NIHF develops due to increased central venous pressure, decreased diastolic ventricular filling, and decreased fetal CO. Among fetuses and newborns with HFNI, mortality rates due to structural heart defects approach 92%. (28)

Preterm birth is common in the HFNI setting, with an incidence as high as 66%, and early birth has been advocated in the past; however, it has now been shown to worsen prognosis and is currently only recommended in the presence of concurrent obstetric indications. (28) In the scenario of worsening NIHF and fetal CO greater than or equal to 34 weeks, delivery can be considered; however, in the absence of clinical deterioration, delivery at 37 to 38 weeks GA is recommended. (28) If NIHF is caused by heart failure, delivery may be considered if GC is appropriate and the underlying pathology is treatable or reversible. (18) Immediate hemodynamic instability may occur after delivery and preparations should be made for the potential need for mechanical or cardiopulmonary cardiac support. (18)

Fetal arrhythmias such as supraventricular tachycardias and complete congenital heart block (CCB) can cause HFNI, preterm birth, and perinatal morbidity. (18) Preterm delivery may be considered in cases of fetal bradycardia or tachycardia in which transplacental therapy has failed and declining fetal health is demonstrated. However, the complications of preterm birth must be weighed against the feasibility, effectiveness, and availability of therapies. (18) Acute intervention in the delivery room may be necessary, including electrical or medical conversion to sinus rhythm if tachyarrhythmia is present, initiation of a chronotropic agent, pacemaker (if bradyarrhythmia is present), or surgical placement of a pacemaker in cases of CHB with hemodynamic compromise. (18)

Other specific cardiac lesions, such as Ebstein’s anomaly, merit consideration for early delivery, depending on the status of the fetus. Although rare (<1% of all CHDs in live births, 3%–7% of fetal CHDs), Ebstein’s anomaly is associated with high perinatal mortality, up to 45% among patients diagnosed prenatally. (29)

Ebstein’s anomaly represents global right ventricular myocardial disease, which causes tricuspid valve malformation, including apical displacement of the annulus and decreased leaflet mobility. (30) When diagnosed prenatally, close monitoring of the fetus is warranted due to the risk of tricuspid regurgitation, cardiac dysfunction, dropsy, and fetal death. (30)

Early delivery may be considered in cases of Ebstein’s anomaly in the presence of dropsy and uncontrolled arrhythmias; However, recent studies suggest worse outcomes with preterm birth. (30) After birth, these patients may suffer hemodynamic compromise, respiratory distress, or cyanosis. (30) There is no current recommendation for in utero treatment, but delivery of the gestation at term at a tertiary center where early postnatal cardiac surgery is available is recommended. (29)

Although most CHDs are hemodynamically stable in utero and at birth, certain critical congenital heart diseases require immediate postnatal intervention.

These lesions include SHCI or d-TGA with a restrictive foramen ovale, CHB with hydrops, endocardial fibroelastosis or low ventricular rate, uncontrolled tachyarrhythmias with hydrops, Ebstein’s anomaly with hydrops, obstructed total anomalous pulmonary venous return, and tetralogy of Fallot with pulmonary valve. absent with severe airway compression. (18) Early planning between 38 and 39 weeks of gestation may be considered in circumstances that justify delivery at a specific cardiac center and extensive coordination of multiple interventionists and specialists. (18)(26)

The relative immaturity of myocardial structure and function in full-term neonates relative to older infants and children is well known. These problems are amplified in premature newborns. Furthermore, in preterm neonates with the potential for left-to-right shunting, underdeveloped pulmonary arterioles may allow a more rapid decrease in pulmonary vascular resistance and an increase in postnatal pulmonary overcirculation compared to full-term neonates with similar cardiac lesions. . (31)

Postnatal cardiac imaging evaluation of infants with suspected CHD typically begins with echocardiography, while other imaging modalities such as computed tomography angiography (CTA), cardiac magnetic resonance imaging (MRI), and cardiac catheterization may be considered to specific injuries.

The risks and benefits of each mode must be considered, especially in premature babies. With high-resolution transducers, portability, relatively low cost, and lack of radiation exposure, echocardiography should be considered the first-line imaging modality in suspected neonatal CHD and is often the only imaging mode necessary for clinical decision making. (32)

In premature infants, potential limitations of echocardiography include poor acoustic windows, clinical patient instability, and limited visualization of extracardiac structures. Prematurity may also preclude the use of intraoperative transesophageal echocardiography given limitations in available transesophageal probe sizes.

Although echocardiography can provide detailed definition of intracardiac anatomy, CTA may be considered for better imaging of extracardiac structures, such as the aorta and its branches, coronary arteries, distal pulmonary arteries, systemic and pulmonary veins, or airway abnormalities. . (33)

Three-dimensional images can further delineate anatomy, providing optimal surgical planning, and their use has become more prevalent. (33) The benefits of ACT include high spatial and temporal resolution, elimination of the need for sedation due to rapid acquisition times, and potential avoidance of other more invasive procedures such as cardiac catheterization. (3. 4)

Risks of ACT include radiation exposure, although recent developments in cardiac ACT technology allow for reduced radiation dosage. (35) However, neonates are more sensitive than adults to radiation-induced malignancies, and radiation exposure should be considered. (33) CTA requires up to 15 times less radiation than cardiac catheterization. (35) The risk of contrast nephropathy should also be considered in premature neonates born before 34 weeks GA undergoing CTA, as their renal function may be impaired due to abnormal and incomplete nephrogenesis. (36)

Premature infants with CHD may have limitations and challenges, such as smaller body size and increased heart rate, which can make CTA imaging more difficult. (33)

Cardiac MRI may be useful in measuring cardiovascular function and may provide additional value to echocardiography. (37) Indications for cardiac MRI in the neonate include borderline ventricular hypoplasia, cardiac tumors, and congenital cardiomyopathy. In the setting of borderline left ventricular hypoplasia, cardiac MRI may provide more accurate estimates of left ventricular volumes and may help plan the initial palliation of a single versus double ventricular repair. (32)

Cardiac MRI evaluation may be useful in the diagnosis of cardiac tumors, potentially allowing the patient to avoid surgical biopsy. (32) Similar to CTA, cardiac MRI can also provide visualization of extracardiac structures, such as pulmonary veins and systemic veins, pulmonary arteries, and the aorta. (32) Disadvantages of cardiac MRI include cost, procedure duration, limited availability, exposure to contrast agents, and possible need for sedation.

Although advances in echocardiography and increased availability of cardiac MRI and CTA have decreased the need for cardiac catheterization for structural evaluation, it remains critical in cases requiring intervention or physiologic evaluation. In the setting of d-TGA or SHCI with restrictive foramen ovale, cardiac catheterization with balloon atrial septotomy may be necessary. (38)

Other potential indications for interventional catheterization in the neonatal period include balloon valvuloplasty for critical pulmonary or aortic valve stenosis, right ventricular outflow tract stenting in cases of severe pulmonary stenosis, conduit stenting arteriosus in conduit-dependent heart defects and aortic stenting in selected patients with coarctation. (38)

Cardiac catheterization also offers both anatomical and hemodynamic evaluations, providing chamber pressure measurements, oxygen saturation data, and pulmonary vascular resistance data. (32)

Angiography is the gold standard for diagnosing right ventricular-dependent coronary circulation in pulmonary atresia with intact ventricular septum, with important implications for prognosis, risk stratification, and planning of future cardiac interventions. Cardiac catheterization intervention can provide hemodynamic stability to preterm infants with CHD until definitive surgical repair can be performed.

The risks of cardiac catheterization are not insignificant, especially in smaller and premature babies, and include direct damage to surrounding vessels and structures, thrombosis, stroke, anesthesia risk, nephropathy, and patient discomfort. (32)(33) Other limitations of catheterization procedures in preterm infants include the size of the equipment, limited vascular access, and technical difficulty of the procedure.

Data on the outcomes of cardiac catheterization in premature infants are limited, and data involving low birth weight (LBW) infants have demonstrated variable results. A study of infants with CHD from 8 centers who were less than 1 year old demonstrated a significantly increased risk of catheterization-related adverse events and a more than 10-fold increase in mortality in infants weighing less than 2000 g compared with infants in higher weight categories. (39)

Another smaller but more recent study focusing on infants weighing less than 2500 g demonstrated a mortality rate of 0.46% and risk of major morbidity of 5% (less than the previously reported morbidity rate of 6.8). % in patients weighing > 5000 g). (39)(40) More research is needed to better understand the risks and outcomes of cardiac catheterization in premature infants.

Preoperative care of preterm infants with CHD is complicated by the multiorgan impacts of prematurity, many of which can affect the cardiovascular system. Additionally, the preoperative phase of care may represent a longer period in preterm infants, as surgical intervention is frequently delayed to optimize growth and development. (10) For infants with isolated CHD born at lower gestational ages, mortality increases in the neonatal and early postnatal period, making this a particularly vulnerable period and a potential target for optimization of management. (9)

The challenges of preoperative management of preterm infants with CHD are multifaceted. Issues that will be addressed in this section include complexities of the immediate postnatal physiologic transition, conduit-dependent lesions, and hemodynamic monitoring of the preterm infant with CHD. It should be noted that preoperative nutrition management is an important and nuanced topic that is discussed in a later section.

The transition from fetal to extrauterine circulation is a delicate process that is based on the intrinsic response of the newborn to environmental changes. The first breaths after birth are often accompanied by a dramatic hemodynamic change involving changes in systemic and pulmonary preload and afterload. The physiological stress of this process is magnified in premature infants with immature organ systems and is further complicated by the presence of CHD.

The myocardium of premature neonates has fewer contractile elements, higher water content, and greater dependence on L-type calcium channels, which depend on extracellular calcium rather than calcium stores in the sarcoplasmic reticulum. (41) For these reasons, premature newborns with CHD may be more susceptible to circulatory problems in the transition phase.

ACOG recommends delayed cord clamping (PRC) in vigorous preterm neonates. (42) Multiple meta-analyses have demonstrated the benefits of PRC, including a lower incidence of late-onset sepsis, fewer blood transfusions, improved postnatal blood pressure, decreased use of vasoactive medications, and a significantly lower incidence of intraventricular hemorrhage (IVH). Data also suggest that PRC in term neonates with CHD is safe and feasible; However, more research is needed to determine the safety and usefulness of PRC in preterm infants with CHD. (43)(44)

As mentioned above, some cardiac lesions are sustained by fetal physiology, but after birth, newborns with CHD are susceptible to significant hemodynamic compromise. PGE1 is a crucial medication used to maintain patency in neonates with ductal-dependent CHD who require increased either systemic or pulmonary blood flow, or improved mixing of oxygenated and deoxygenated blood. Its use is of particular importance in premature neonates in whom the duration of PGE1 may be longer than in full-term neonates, since cardiac surgery is often performed later. (45) However, this medication has numerous potential side effects including apnea, hyperthermia, hypotension, leukocytosis, seizures, electrolyte imbalances, and necrotizing enterocolitis (NEC). (46)

Complications that may be seen with prolonged infusions include gastric outlet obstruction and cortical hyperostosis. (46)(47) Apnea related to PGE1 infusions can be seen in up to 22% of full-term neonates and up to 67% of preterm neonates while most of the remaining side effects are minor. common. (45)(48) Both caffeine and theophylline have been shown to decrease PGE1-induced respiratory depression, however, caffeine may do so with lower rates of adverse effects such as tachycardia and food intolerance. (49)(50) Furthermore, there may be a dose-dependent relationship between PGE1 and respiratory depression. Therefore, PGE1 infusions at lower doses (e.g., 0.01–0.03 mg/kg per min) should be considered in preterm infants at increased risk of developing apnea. (fifty)

Hemodynamic monitoring of the premature neonate with CHD is an essential but complex component of preoperative management, made more challenging by the immaturity of the cardiovascular and other organ systems. Traditional monitoring techniques, including invasive and non-invasive blood pressure, capillary refill time, and core-periphery temperature difference, have proven to be unreliable surrogates for CO assessment.

An integrated approach involving traditional vital sign monitoring and newer assessments of CO and systemic perfusion may be beneficial. Blood pressure monitoring is an inadequate measure of perfusion when used in isolation due to the transition in neonatal physiology and normative blood pressures are not yet clearly established in this patient population. (51)

Urine output may also be an unreliable indicator of perfusion, as immature renal tubules cannot absorb solutes and water as effectively, leading to a relative increase in urine output. Serial monitoring of blood gases and lactate are useful tools in the evaluation of respiratory function and the adequacy of systemic oxygen delivery.

Echocardiography, although an effective means of assessing cardiac function, may overestimate CO in the setting of left-to-right shunts, and its use has not been shown to improve outcomes. (41) Superior vena cava flow can be measured with Doppler echocardiography techniques and correlates moderately well with CO. (52)

Near-infrared spectroscopy (NIRS) uses differential absorption of red and infrared light by oxygenated and deoxygenated hemoglobin to assess regional oxygen delivery; NIRS values ​​have been shown to correlate well with central venous saturation. (51) However, normative values ​​for NIRS have not yet been established in the premature newborn, and this modality may be more useful as a regional oxygenation trend and not as an absolute number.

Newer techniques for assessment of regional oxygen delivery include amplitude-integrated electroencephalography, which is most widely used as a means of assessing cerebral oxygen delivery in preterm neonates. Laser-Doppler flowmetry measures peripheral microvascular blood flow and has been shown to positively correlate with cardiac function and disease severity. (53) Electrical cardiometry for non-invasive evaluation of GC and dark field imaging to evaluate regional perfusion are 2 new techniques that need further study to evaluate their clinical applicability. (51)

Awareness of the physiological impact of prematurity in infants with CHD is important for optimizing clinical management, standardizing care, and improving patient outcomes. Lower CO, lower birth weight, and impaired multiorgan development may have a potentially negative impact on the surgical/interventional candidacy of preterm infants with CHD and are associated with an increased risk of morbidity and mortality. (21)(54) In addition to the morbidities directly related to surgical repair of CHD, there are a number of morbidity considerations related to prematurity itself. (55)

Neurodevelopmental impairment is the most significant consequence for survivors of severe CHD, and preterm birth has an adverse impact on this important morbidity. (56)(57) The increased risk of neurocognitive deficits is in part related to prenatal factors and abnormal circulatory physiology, resulting in altered fetal brain development.

Third trimester fetuses with some forms of complex CHD including d-TGA and SHCI have lower GA and weight-adjusted total brain volumes than fetuses that grew appropriately without CHD. (58) There is also evidence of delayed neuroaxonal development, white matter injury, and altered metabolism in fetuses with some forms of complex CHD compared to those without CHD. (58)(59)

MRI and magnetic resonance spectroscopy findings in full-term neonates with some forms of complex CHD are similar to those in preterm neonates born 1 month before full term, supporting a delay in brain development of approximately 4 weeks of gestation. (59) Risk factors for HIV in newborns with CHD include lower CO, lower birth weight, late cardiac surgery, and use of extracorporeal membrane oxygenation.

It is estimated that up to 50% of severe CHD survivors (both term and preterm) will demonstrate some degree of neurodevelopmental delay. (60) These delays can be attributed to microcephaly, structural brain immaturity, right-to-left intracardiac shunt that can result in decreased cerebral oxygen supply, need for extracorporeal life support, or low CO. (57)(61)(62)(63)

Supportive care is a model of care used in many NICUs and has been associated with reduced length of stay, transition to early oral feeding, and improved neurodevelopmental outcomes in preterm infants. (64)(65) Evidence-based developmental care practices include core measures to support the following areas: assessment of sleep, pain, and stress; management of daily living, including positioning and feeding; neonatal skin care; family-centered care; and a healing environment, including modifying factors such as lighting and temperature.

It is important to maintain consistency in the provision of developmental supportive care across all units in which premature infants are being cared for, including the NICU, cardiac intensive care unit, and cardiac acute care unit.

Prematurity and CHD are also important risk factors for the development of NEC. (66)(67)(68) Disruption of splanchnic blood flow due to abnormal cardiovascular physiology, hypoxia, and low CO in newborns with CHD is hypothesized to contribute to poor intestinal perfusion and increased incidence of NEC. (69) In duct-dependent CHD, diastolic drainage and decreased CO further contribute to mesenteric hypoperfusion. (70)(71)

The rate of NEC is several times higher in infants with CHD, with considerably high rates in patients with cardiac lesions causing compromised systemic output (eg, critical aortic stenosis, coarctation of the aorta, hypoplastic left heart, and interrupted aortic arch). or increased diastolic drainage (e.g., truncus arteriosus and aortopulmonary windows), and in those born prematurely or in VLBW newborns. (68)(72)

The provision of enteral nutrition in preterm infants with CHD remains a key area for targeted improvement. However, enteral feeding practices in preterm infants with CHD are inconsistent across providers and hospital systems, especially when patients receive PGE1, pharmacologic support for hypotension, or indomethacin. (73)(74) It is estimated that up to half of clinicians restrict enteral feeding in infants receiving PGE1 despite the lack of convincing evidence that PGE1 increases the risk of NEC. (72)(75)

Previous publications have outlined clinical guidelines for perioperative feeding in the neonatal CHD population. (70)(73)(76)(77)(78)(79) The focus on the preoperative period includes serial feeding assessments and hemodynamic evaluations to guide the timing of initiation and progression of enteral nutrition.

Human milk is strongly preferred for premature infants as it contains immunomodulatory components that enhance innate defense immunity, thereby reducing the risk of NEC and sepsis, improving feeding tolerance, and reducing the duration of hospitalization. (80)(81)(82)

A randomized controlled trial also demonstrated long-term improvement in right and left ventricular end-diastolic volume index and stroke volume index and beneficial long-term cardiovascular outcomes in preterm infants fed human milk. (83)

Pasteurized donor human milk is increasingly being recognized as an alternative in the absence of an adequate breast milk supply. A recent retrospective single-center cohort study demonstrated that an unfortified human milk diet (mother’s own milk or donor human milk) was associated with a statistically significant reduction in the risk of preoperative NEC in infants with complex CHD. after controlling for multiple covariates. (84)

In the postoperative period, the use of parenteral nutrition is recommended with the initiation of human milk feeding as soon as hemodynamic and cardiac stability is achieved. Institution-specific feeding advancement protocols should be used in collaboration with a multidisciplinary feeding team, including registered dietitians and trained feeding experts, to incorporate assessment of vocal cords and swallowing function. (85)

The timing of surgical treatment of CHD in prematurity deserves special consideration. Although difficult to quantify, experienced cardiac surgeons are always under the impression that cardiovascular tissues are very delicate and relatively unfavorable for surgical manipulation in premature neonates relative to those in full-term neonates. However, as noted above, the transition from fetal to postnatal cardiovascular physiology involves hemodynamic changes that often unmask the detrimental effects of CHD. Therefore, physicians caring for premature patients with CHD face the dilemma of balancing the risks of early surgery with the risks of untreated heart defects.

As discussed in more detail in the results section, the risk of cardiac surgery in premature patients is considerable. (86)(87) However, it is unknown whether early surgery or a “feed and grow” strategy pending a higher corrected GA leads to better outcomes.

A single-center study of 149 infants with critical CHD and a birth weight of less than 2 kg found no difference in early survival when comparing an early surgery strategy versus a period of feeding and growth before surgery. (88)

The optimal timing of surgery also depends on the type of surgery needed. In principle, the types of surgery can be classified as anatomical correction, physiological palliation or heart transplant. Anatomical correction aims to repair the congenital heart defect. For example, a ventricular septal defect could be closed with a patch.

Unlike physiological palliation which aims to establish hemodynamics that improves patient outcomes without correcting the underlying defect. For example, SHCI is usually palliated with a Norwood operation to remove left ventricular outflow tract obstruction, followed by a bidirectional superior Glenn cavopulmonary connection to unload the right ventricle and a total Fontan cavopulmonary connection to normalize saturation. systemic oxygen. (89)

Operations involving the use of cardiopulmonary bypass (CPB) can be particularly challenging in premature patients. It is important to note that the blood volume in premature newborns is approximately 90 ml/kg. (90) Therefore, the amount of volume required to prime the BCP circuit may be several times greater than the circulating blood volume of a premature neonate. This dilutes the newborns’ own blood and increases the inflammatory response by exposing the blood to a relatively larger artificial surface area. (91) Therefore, operations without BCP may be preferable in very premature patients.

Of particular interest is the use of the so-called hybrid procedure for premature neonates with SHCI and related variants. An alternative to the standard stage I Norwood procedure is a hybrid operation that involves placing bilateral pulmonary artery bands and a ductus arteriosus stent, both of which can be done without the use of BCP.

A 2015 study based on data from the Society of Thoracic Surgeons for Congenital Cardiac Surgery (STS-CHS) database evaluated the hybrid procedure versus Norwood surgery for initial palliation of SHCI. This study indicated that although the majority of infants with SHCI underwent the Norwood operation as the index procedure, the hybrid procedure was used more frequently in preterm infants. More specifically, 23% of babies who underwent the hybrid procedure were born premature compared to only 9% of babies who underwent the Norwood procedure as their index procedure. (92)

The hybrid procedure is used in some centers as the primary option for initial palliation in all patients with SHCI and in other centers as the intervention of choice for certain high-risk patients (including those born preterm). Institutions with lower SHCI caseloads and higher Norwood mortality rates tend to use the hybrid procedure more frequently compared to the Norwood procedure for stage 1 SHCI palliation. (92)

The main advantage of the hybrid procedure is the avoidance of BCP in smaller and/or sicker patients; However, data showing that the hybrid procedure improves outcomes in preterm infants are scarce. (93) Other operations that do not require CPB are palliative operations such as pulmonary artery banding and Blalock Taussig Thomas shunt, or corrective operations such as coarctation repair via thoracotomy.

Although the outcomes of neonatal cardiac surgery have generally improved, birth with earlier GA and low birth weight remain recognized as important risk factors for in-hospital mortality. Premature infants with CHD show a 3- to 4-fold increase in mortality and an increased risk of neurodevelopmental disorders. (5)(9)(14)(21)(94) Additionally, operative mortality rates in preterm infants undergoing open cardiac surgery for CHD are higher compared to operative mortality rates in full-term infants. . (95)(96)(97)

LBW (<2.5 kg), VLBW (<1.5 kg), and extremely LBW (<1 kg) infants with CHD have a 1.5 to 4 times higher risk of mortality than those of comparable birth weight whose medical burden is only prematurity. (14)(98)(99)(100)

A recent analysis of 513 premature patients (<37 weeks gestation and birth weight <2.5 kg) undergoing cardiac surgery showed a 6-fold increased risk of mortality compared with full-term infants matched for heart disease diagnosis. (101) Recently, published data from a large multicenter clinical registry indicate that young infants with CHD who have relatively minor degrees of fetal growth restriction, as evidenced by birth weight Z score less than 0.5, have a increased risk of morbidity and mortality, particularly those born early term. (102) Furthermore, premature newborns with low Apgar scores and requiring invasive ventilatory support have a higher risk of mortality when more complex procedures are required for CHD. (103)(104)(105)

Evidence is emerging for a negative linear relationship between mortality in infants with CHD and GD. (22) One study demonstrated a 1-year mortality rate of 41.4% in premature infants with critical CHD born at less than 29 weeks GA, with a gradual improvement in mortality rates seen with increasing GA. (97) Babies born between 39 and 42 weeks GA had a 1-year mortality rate of 8.9%. (97)

A recent analysis of data from the STS-CHS database found increased in-hospital mortality, higher rates of postoperative complications, and increased length of stay for early-term neonates undergoing cardiac surgery (37-38 weeks of age). full gestation) compared to a reference group of 39.5 weeks. (twenty-one)

Similar results were demonstrated in a single-center study that showed 2.3 times higher odds of mortality in infants with CHD born at 37 to 38 weeks of gestation compared with those born at 39 to 40 weeks of gestation. (13) Data from both studies were adjusted for weight, suggesting that other characteristics of early term birth contribute to worse postoperative outcomes. Some proposed mechanisms of increased morbidity and mortality in this population include changes in the respiratory system that occur late in gestation, as well as energy reserves, enzyme function, and immature immune systems.

Notably, current data also demonstrate significantly higher rates of postoperative complications and increased morbidity in preterm and early-term neonates with CHD, including NEC, seizures, IVH, periventricular leukomalacia, and BPD. (21)(94)(97) Babies with CHD who are born preterm and late preterm are also more likely to be discharged from the hospital with supplemental oxygen and enteral feedings. (94)

Other investigations focusing on long-term outcomes after neonatal cardiac surgery have demonstrated trends in neurodevelopmental outcomes and transplant-free survival in children born preterm and early term with CHD.

Neurodevelopmental testing performed at 2 years corrected age in CHD survivors born preterm who undergo neonatal cardiac surgery demonstrated higher rates of cerebral palsy in the preterm population with CHD compared to patients born preterm without CHD and compared to patients born at term with CHD. (106) Furthermore, preterm infants with CHD had lower functional and neurodevelopmental scores (particularly affecting self-care skills and language skills) compared to patients born preterm without CHD. (106)

Neurological evaluations of adolescents with single ventricle heart disease who underwent the Fontan procedure demonstrated that those born early term (37-38 weeks GA) had a higher prevalence of executive dysfunction and psychiatric problems compared to their full-term counterparts. . (107)(108) Another study of patients with SHCI found that even when babies survived Norwood hospitalization, preterm birth was independently associated with decreased transplant-free survival at 6 years of age. (109)

Given the challenges of assessing and managing CHD in preterm neonates and the associated imperfect outcomes, numerous issues require further investigation. Interventions to decrease the likelihood of preterm birth and late preterm birth and measures to prolong gestation should be further explored and implemented where reasonable. (10) Furthermore, a growing body of research indicates the important role that the maternal-fetal environment plays in the outcomes of neonates with complex CHD. (19) (110)

More research is needed to better understand the interaction between maternal health conditions such as hypertensive disorders of pregnancy and fetal growth and preterm birth. Studies exploring risk stratification of outcomes of preterm and preterm infants with CHD based on the reason for prematurity (maternal vs. fetal indication) and type of CHD are warranted for optimization of patient care. (10)

A multidisciplinary approach to the care of this population in both the prenatal and postnatal periods involving collaboration between maternal-fetal medicine, neonatology, and pediatric cardiology is integral to achieving this goal. Finally, there are many aspects of postnatal care of the preterm infant with CHD that warrant additional study of noncardiac organ systems, accurate perioperative hemodynamic monitoring, and surgical timing and techniques.