Sonographic evaluation of adrenal size in neonates (23 to 41 weeks of gestation)

With the advent of ultrasonography (US), many authors have studied the sonographic appearance and measurement of normal fetal adrenal gland in utero [1‐4]. These studies showed that fetal adrenal gland size is positively correlated with both gestational age and estimated body weight. In neonates, US has been shown to provide a useful method of evaluating the appearance of the adrenal glands to diagnose pathologies such as adrenal hemorrhage and hyperplasia [5, 6]. However, regarding postnatal adrenal size, some authors reported sonographic evaluation in the late 1980s, but the focus was solely on the change in size postnatally, based on marked involution of the fetal zone component during the early weeks and months of extrauterine life [7, 8].

During the last two decades, the advances in the field of US have enabled higher resolution display and precise quantitative measurement of the organ dimensions.

Recently, it has been recognized that some very preterm infants develop acute profound primary circulatory failure that responds to glucocorticoid therapy, and a relationship between hypotension and relative adrenal insufficiency in preterm infants has been discussed [9, 10]. Previous findings demonstrated that preterm infants born before 30 weeks of gestation have a higher risk for the development of, not only chronic lung disease, but also early adrenal insufficiency in comparison to infants born after 30 weeks of gestation [5, 11].

The objective of the present study was to demonstrate adrenal gland size in extremely preterm to term neonates in a specially designed prospective study, and to compare adrenal gland size between preterm and term infants to estimate the impact of prematurity and perinatal factors.

The author prospectively assessed the relationship between neonatal adrenal gland size, as measured by 2-dimensional (2D) US, and perinatal factors. Written informed parental consent was obtained.

A total of 374 neonates were admitted to our NICU during the study period between April 2009 and March 2011, and 350 of these neonates met the inclusion criteria. Among the excluded 24 infants, 17 were outborn, 5 had major congenital anomalies, and the parents of 2 did not agree to participate. Two infants had intrauterine cytomegalovirus infection with severe brain anomaly and were excluded because of the presence of major congenital anomalies. There was no infant whose adrenals were not ultrasonographically examined in the first 3 h of life. In the enrolled 350 consecutive neonates (male/female ratio, 172:178), the median GA was 36.3 weeks, with an interquartile range (IQR) of 33.5 to 38.4 weeks, and the median BW was 2156 g, with an IQR of 1744 to 2847 g. Among the subjects, none was subsequently diagnosed with congenital adrenal hyperplasia, adrenal hemorrhage, or primary adrenal tumor (e.g. neuroblastoma).

The measurement of neonatal adrenal gland has been the subject of only a few previous ultrasonographic studies, with the latest report published in the early 1990s [7, 8, 13]. Various methods of measuring the adrenal size using US have been described because of the irregular shape of the gland. These include measurements of adrenal length, width, and circumference [7, 8, 13, 15‐17]. In the present study, the adrenal area measurements were chosen. The author found only one study about the evaluation of adrenal size by adrenal area, which was conducted in the 1980s [8]. In addition to the multipart shape of the gland, insufficient resolution of the US device at that time resulted in difficulty in obtaining accurate information on the anatomical size of the glands. With the advent of the resolution and trace technology of US, it was possible to measure the adrenal area with higher accuracy than in the past. Therefore, as a measurement parameter to estimate the actual adrenal size, adrenal area might be preferable to adrenal length or width. Previously, we evaluated adrenal size by measurements of the adrenal area and demonstrated that the adrenal area could be measured in all neonates born after 23 weeks of gestation [12]. In the present study, although the author evaluated a larger number of subjects than in the previous study, the right adrenal gland was seen and measured in the assessment, without difficulty, in all study subjects.

In the present study, cAI was calculated to investigate the correlation with GA. A peculiar pattern was found between cAI in preterm infants with a GA below 30 weeks and in those with a GA above 30 weeks. cAI was negatively correlated with GA up to 30 weeks, whereas it remained almost constant from 30 weeks to term. Previously, Kangaloo et al. demonstrated in their ultrasonographic study that the length of the adrenal gland was directly correlated with GA up to 32 weeks of gestation, after which no significant increase in the length of the gland occurred to full term [13]. There might be some functional differences in fetal adrenal gland around 30 weeks of gestation. In the present study, however, the intergroup and intragroup comparisons among the 3 groups could not identify any significant perinatal factors that could explain why the correlation patterns between cAI and GA differed between before and after 30 weeks of gestation.

The fetal adrenal gland develops and exhibits a marked change in size, structure, and function during the fetal and perinatal periods. The fetal adrenal cortex consists of three compartments: the relatively large, inner fetal zone (FZ), the outer definitive zone (DZ), and the intermediate transitional zone (TZ). The FZ mainly produces androgens, the DZ produces mineralocorticoids, and the TZ contains enzymes for cortisol production [18]. The fetal adrenal cortex grows rapidly from approximately 10 weeks of gestation to term almost entirely owing to the enlargement of the FZ. Subsequently, the adrenal size almost equals that of fetal kidneys by 20 weeks of gestation, and the weight doubles between 20 and 30 weeks [19]. In contrast, the DZ growth occurs owing to hyperplasia by 10 to 12 weeks of gestation. Subsequently, the TZ cells, which differentiate from the definitive cortex, have the capacity to synthesize cortisol. By 30 weeks of gestation, the DZ and TZ begin maturation into the zona glomerulosa and the zona fasciculata, respectively [19]. Fetal adrenal size exhibits disproportionality relative to body weight throughout the entire growth process. The present study plainly showed that fetal adrenal growth might greatly change after 30 weeks of gestation.

Considering adrenal functions, Bolt et al. showed in their study that the cortisol response to adrenocorticotropic hormone stimulation in infants born before 30 weeks of gestation was significantly lower than in more mature infants [20]. Moreover, Heckmann et al. demonstrated that the severity of illness did not have a significant influence on cortisol production rates in preterm infants born before 30 weeks of gestation, and they concluded that cortisol production rates in such immature infants might reflect inadequate stress reaction [21]. Grofer et al. demonstrated a maturation of the adrenal stress response in infants born after 30 weeks of gestation by showing a positive association between severity of illness and cortisol production rate in those infants, unlike in more immature infants [22]. The hormonal demands of growth and maturation in premature infants need to be balanced with those of acute critical stress. However, this process is not yet complete in a preterm infant born before 30 weeks of gestation. Fetal mechanisms regulating glucocorticoid homeostasis might persist after birth to protect such immature infant from excessive glucocorticoids [23]. Recently, relative adrenal insufficiency has been discussed in the preterm infant born before 30 weeks of gestation [24]. This could be explained by the above-mentioned immature adrenal function of such preterm infants. It is thought that the developmental process of fetal adrenal function might support the change of the cAI shown in the present study. A limitation of this study is that the data collected about the mode of delivery included only whether cesarean section (CS) was performed or not, rather than including all the details. Especially in extremely preterm delivery, CS is often performed after the onset of labor. Turan et al. have suggested that the premature onset of labor has a relationship with fetal adrenal gland enlargement [4]. Therefore, the result may be influenced by the fact that the delivery occurs before or after the onset of labor.

In this study, especially in term neonates, there were significant correlations between cAI and both fetal distress and low 1-min Apgar score, that is, adrenal enlargement was associated with a clinical history of perinatal distress. A similar sonographic feature has been previously reported by some investigators [25‐27]. Their histological studies postulated that adrenal enlargement was caused by adrenal congestion. Perinatal stress like asphyxia causes a redistribution of cardiac output to preserve blood flow to the more vital organs such as the brain, heart, and adrenal glands, and the consequent congestion may increase the pressure within the capillary network [27]. As hypoxic events cause damage to endothelial cells and impair vascular autoregulation, hemorrhage or infarction can occur in these organs, and probably in the adrenal gland [27]. However, the pathophysiology is not fully understood. Further investigations to demonstrate the causal relationship between perinatal asphyxia and adrenal size are warranted.

The present study demonstrated that the developmental pattern of fetal adrenal gland was different before and after 30 weeks of gestation. In addition, the adrenal area relative to body weight correlated with perinatal asphyxia after 30 weeks of gestation. The results in the present study suggest that the magnitude of adrenal stress response might mature after 30 weeks of gestation.