Coarctation of the aorta is a condition that may appear simple on the surface but has challenged pediatric cardiologists for decades. Coarctation can be an isolated, discrete stenosis of the descending aorta just distal to the left subclavian artery, or it may be a harbinger of more complex anatomic malformations. In either case, optimal management continues to evade the pediatric cardiology community; different experts advocate for aortic balloon dilation, subclavian flap aortoplasty, resection with end-to-end anastomosis, or synthetic patch plasty. The appropriate timing for an intervention can be even more controversial in the extremely premature neonate.
In the fetus, the head and neck vessels are supplied by the left ventricle, whereas the lower body is supplied by the right ventricle via the patent ductus arteriosus. After birth, the ductus arteriosus constricts, and the left ventricle significantly increases its cardiac output to perfuse the entire body. There are two main embryologic theories for the development of coarctation of the aorta: (1) reduced blood flow though the aortic isthmus in the fetus limiting its circumferential growth or (2) circumferential hyperplasia of smooth muscle at the level of the aortic isthmus.
Currently, the diagnosis of coarctation of the aorta in the preterm neonate has tremendous variability given the technical difficulty of acquiring the necessary images and the lack of a standard definition for “normal” size. The Boston Z Score Calculator is a popular tool in congenital cardiology for children of all sizes, but only 40 premature neonates were examined in the process of creating the Z score curves (Steven D. Colan, MD, personal communication, January 2017). The importance of Z scores in the practice of pediatric cardiology is well documented, as is the need for sound statistical methodology when normalizing for body size. There is little doubt that both under- and over-diagnosis of coarctation of the aorta occurs in neonates. In either case, the incorrect decision can have life-long consequences for patients and their families, with the risk of developing necrotizing enterocolitis, renal insufficiency, cerebral intraventricular hemorrhage, or death.
In this issue of the JASE , Dijkema et al. attempt to bring more scientific evidence to the management of aortic coarctation in this challenging patient population. We commend her and her colleagues for addressing this important topic. Rapid growth of the fetus and neonate require all anatomic measurements to be normalized to body size for interpretation, and this is usually accomplished by the calculation of Z scores. However, Cantinotti et al. reviewed over 30 published pediatric echocardiographic nomograms and Z score databases from different institutions and found a very large and concerning discrepancy for the definition of normal. The characterization of normal size must always be evaluated for accuracy and applicability. Do the patients in this trial represent all patients with regard to ethnicity, race, and sex? Are the disease processes of the study patients homogenous or heterogeneous? Is the acquisition of data reliable? Are the data reproducible if the methods are used in my institution?
Can Some Patients Define Normal for All?
The patients enrolled in this study to define “normal” came entirely from one hospital in the Netherlands. Do these extremely premature Dutch patients have the same aortic arch dimensions as those from the United States, Asia, Africa, Latin America, and around the world? Looking at the demographics of the study population, their mean weight and height were equivalent to the 50th and 40th percentiles, respectively, for children of the same gestational age born in the United States. Does this make the data widely applicable to the United Sates and other countries? We know from adult data that women have smaller coronary arteries than men. Similarly, those of Southeast Asian descent have smaller coronary arteries than Caucasians. In pediatric patients, it is known that African-Americans have thicker ventricles, lower systolic volumes, and diminished end-systolic wall stress compared with control patients. Kobayashi et al. demonstrated a gender bias for the internal diameter of the coronary arteries in pediatric patients. The point made by these different studies is that we should be careful when using one patient population to define normal for the entire world. It is important that as a community, we collaborate and continue this important work to increase the scientific validity of normal. The Pediatric Heart Network is currently in the process of performing a large, National Institutes of Health–funded trial to establish a Z score database for common echocardiographic measurements based on a uniformly defined and racially diverse population of normal children from multiple centers over a wide geographic area.
While all the patients in the study by Dijkema et al. had a primary diagnosis of extreme prematurity, there is tremendous heterogeneity as to why patients are born prematurely. It can be the result of maternal factors such as uterine anomalies, rupture of membranes, incompetent cervix, or idiopathic preterm labor. These have very different ramifications than extreme prematurity due to placental or fetal causes such as intrauterine growth restriction, pregnancy induced hypertension, or chorioamnionitis. Fouzas et al. demonstrated that premature neonates with intrauterine growth restriction have left ventricular dilation, ventricular septal hypertrophy, and delayed left ventricular relaxation time. How this affects the aortic arch size is not known. In addition, it is the standard of care for an expectant mother in preterm labor to receive at least two doses of steroids to help with fetal lung maturation. It has been well established that antenatal steroids have positive effects on the fetus’ systemic blood vessels with a significant decrease in the incidence of necrotizing enterocolitis and cerebral intraventricular hemorrhage. Once again, how this affects the size of the aortic arch has not been described. We must be careful not to assume that 385 premature neonates from one institution can accurately define normal for all, considering the significant heterogeneity that exists within this patient population.
How Reliable and Reproducible Are Our Measurements?
Reliable image acquisition and reproducible interpretations of those images is the foundation of congenital cardiology. The smaller the anatomic vessels or chamber being evaluated, the more likely there may be inaccuracy and measurement variability. Obtaining reliable aortic arch images in an extremely premature neonate can be difficult even in the hands of the best sonographers. On the surface, a measurement within 1–2 mm may seem precise, but, to the contrary, it could be the difference between normal and abnormal in this population. While recognizing the precision in the study by Dijkema et al. , with intraclass correlation coefficients of 0.844 for the transverse arch and 0.818 for the aortic isthmus, we must also highlight that 48% of patients had inadequate echocardiographic image quality for measurements on the sixth day of life.
The creation of a Z score depends on normalization to body size, usually based on body surface area, but this study normalized to birth weight. This is understandable given that the length of a neonate, and especially the premature neonate, can be extremely variable, as stated by the authors. However, for this reason, the data from this article could not be cross referenced with the Boston Z Score Calculator, which normalized aortic arch size in premature neonates to body surface area. Although weight is the most objective and reproducible measurement, neonatal practitioners will all agree that in clinical practice there is significant variability between scales within each hospital. A difference of 5%–10% in birth weight from an uncalibrated scale, or from a baby actively moving during the weighing process, can mean the difference between a normal and abnormal Z score.
Finally, we should question the standards applied within our own scientific community. How did we all agree that two standard deviations from the mean is the appropriate definition of normal? If all the patients in this study were evaluated by the clinician and deemed not to have congenital heart disease, then we should expect one of the subjects to have the smallest aortic diameter while being free from the diagnosis of coarctation. However, based on the premise that any aortic measurement with a Z score of −2 is abnormal, we should then expect approximately 9 to 10 patients in this study to be “incorrectly” diagnosed with aortic arch pathology. Did Dijkema et al. refer any of these patients for aortic arch surgery?
The field of medicine is undergoing an evolution with a massive influx of data. All physicians at one point in their career have been guilty of focusing too much on numbers, data, and images to get a sense of our patients’ level of wellbeing. Before acting on measurements alone, we must take a step back, review the entire clinical picture, and decide how to interpret the abnormal measurements as we proceed forward in an effort to provide the best care possible for our patients.
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