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Research Institute of Endocrinology, Reproduction, and Metabolism, Departments of Pediatrics (R.J.B., M.M.v.W., H.N.L., H.A.D.-v.d.W.) and Clinical Chemistry and Endocrinology (C.G.J.S.), VU University Medical Center, NL-1007 MB Amsterdam, The Netherlands; and Department of Chemical Endocrinology, University Medical Center St. Radboud (C.G.J.S.), NL-6500 HB Nijmegen, The Netherlands
Address all correspondence and requests for reprints to: R. J. Bolt, M.D., Department of Pediatrics, VU University Medical Center, P.O. Box 7057, NL-1007 MB Amsterdam, The Netherlands. E-mail: . roel.bolt{at}vumc.nl
Abstract
Small for gestational age preterm infants have a higher risk of neonatal morbidity compared to appropriate for gestational age preterm infants. A diminished adrenal response to stress may be involved in the higher postnatal morbidity. The adrenal cortex response in relation to fetal growth was studied by ACTH stimulation tests in 43 preterm infants (born 
32 wk).
The cortisol and 17-hydroxyprogesterone (17-OHP) responses to 1 µg/kg ACTH were analyzed in relation to birth weight SD scores (BW-SDS) corrected for gestational age, gender, and parity. BW-SDS was significantly associated with the cortisol and 17-OHP response. Infants with the lowest BW-SDS had the lowest cortisol levels after stimulation. No effect of size at birth was found on the ratio between cortisol and 17-OHP. In addition, basal cortisone levels in a single blood sample were higher in infants with the lowest BW-SDS than in infants with higher BW-SDS, but the ratio between cortisol and cortisone was comparable in the two groups.
We conclude that the response of cortisol and 17-OHP to ACTH stimulation in preterm infants is related to fetal growth. The lack of influence of fetal growth on the ratio between cortisol and 17-OHP after ACTH stimulation suggests that the activities of 21- and 11ß-hydroxylase are not affected. The lower adrenal response to stimulation may be important in neonatal morbidity and possibly the development of disease in later life in growth-restricted preterm infants.
PRETERM INFANTS WHO are growth restricted in utero have increased rates of mortality and morbidity after birth regardless of gestational age (1, 2). The risk of adverse outcomes, such as respiratory distress and neonatal death, increases with decreasing birth weight percentiles among preterm infants (1). In addition, respiratory distress in preterm infants is directly related to both the birth weight percentile and gestational age (1).
Respiratory distress and subsequent chronic lung disease of prematurity, cardiovascular instability, and/or neurological complications remain the most important determinants of increased neonatal morbidity among preterm infants. Recently, several investigators have suggested that the adrenal cortex may be important in neonatal morbidity in preterm infants (3, 4). A low secretory capacity of the adrenal cortex may cause a diminished stress response during acute illness in preterm infants and could lead to increased morbidity in these infants. Previously we have shown that in appropriate for gestational age (AGA) preterm infants the function of the adrenal cortex is closely related to the duration of gestation and may be important in neonatal morbidity (5). It is unknown whether the increased morbidity in small for gestational age (SGA) preterm infants compared with AGA preterm infants is related to adrenal function as well.
In SGA preterm infants restriction of fetal growth may have a superimposed effect on the function of the adrenal cortex. We hypothesize that adrenal function may be affected by intrauterine growth. We therefore investigated the response of the adrenal cortex to ACTH stimulation in preterm infants in relation to fetal growth.
Subjects and Methods
Subjects
The study group consisted of 43 preterm infants with gestational ages ranging from 25–32 wk, and birth weights (BW) ranging from 526-1985 g. Patients were eligible to enroll after admission to our neonatal intensive care unit. All required respiratory support (high frequency ventilation, conventional mechanical ventilation, or continuous positive airway pressure) during the first week of life. Patients were excluded if they were asphyxiated at birth, had major congenital anomalies, or suffered from life-threatening illness. All infants studied had an arterial and/or venous indwelling catheter and had not received packed cell transfusions 2 d before the test and/or had not received postnatal treatment with corticosteroids. The clinical data of the patients are summarized in Table 1
. The score for neonatal acute physiology (SNAP) was used as an indication of the severity of disease in preterm infants (6). The intensive care period included the number of days the infants stayed in our neonatal intensive care unit. The total number of hospital days was calculated until discharge home. Chronic lung disease at 28 d was defined according to the criteria of Bancalari et al. (7), and chronic lung disease at 36 wk postnatal age was defined according to Shennan et al. (8).
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Testing protocol
ACTH test. To minimize the possible influences of birth-associated stress, antenatal steroid (ANS) treatment because of premature labor, and severe morbidity, an ACTH stimulation test was performed between the 5th and 12th d of life only in infants who were clinically stable and did not show any clinical or laboratory sign of infection. After basal blood sampling, ACTH (tetracosactide, Synacthen, Ciba-Geigy, Roosendaal, The Netherlands) in a dose of 1 µg/kg BW was administered iv between 0800–0900 h (without the use of additional plastic tubing connections and after flushing the heparinized indwelling iv cannula with 0.9% NaCl). The dose was obtained by dilution of ACTH in normal saline and was prepared within 20 min of administration. Blood samples (each 0.3 ml) were withdrawn just before as well as 30 and 60 min after ACTH administration for the determination of cortisol and 17-hydroxyprogesterone (17-OHP) levels. 17-OHP was chosen as a determinant of the capacity of the adrenal cortex to convert steroid precursors, and cortisol was chosen as the final product of glucocorticoid synthesis. Although a complete evaluation of the adrenal cortical function requires the simultaneous determination of several hormones (e.g. dehydroxyepiandrosterone sulfate and 11-deoxycortisol), blood sampling in preterm infants is limited because of the small blood volume and frequent blood sampling during neonatal intensive care treatment.
Basal levels. To evaluate the activity of 11ß-hydroxysteroid dehydrogenase (11ßHSD) in the adrenal cortex, an additional blood sample was taken at 0800 h between the 4th to 14th d of life to evaluate the levels of cortisol and cortisone simultaneously.
Hormone assays
Blood samples were allowed to clot for 15 min at room temperature. Serum was separated and stored at -20 C until analysis.
ACTH test. Serum cortisol was determined in duplicate by RIA (Coat-A-Count, Diagnostic Products, Los Angeles, CA). Serum 17-OHP was determined in duplicate by a competitive ELISA (DRG Instruments, Marburg, Germany) directly in serum without an extraction step because of limited blood sample volumes in preterm infants. Therefore, steroids originating from the fetal zone of the (immature) adrenal cortex, such as 17-hydroxypregnenolone sulfate, were not removed and could contribute to the 17-OHP values because of cross-reactivity (9). However, the levels of cross-reaction of other steroids, including dehydroepiandrosterone sulfate and cortisol, were less than 0.05%, with the exception of 11-desoxycortisol (1.4%) and progesterone (1.2%). The detection limit was 30 nmol/liter for cortisol and 0.5 nmol/liter for 17-OHP. The intra- and interassay coefficients of variation were 5% and 7%, respectively, at a cortisol level of 550 nmol/liter, and 4% and 7%, respectively, at a cortisol level of 1000 nmol/liter. For 17-OHP the intra- and interassay coefficients of variation were 8% and 16%, respectively, at a 17-OHP level of 3 nmol/liter, and 4% and 11%, respectively, at a 17-OHP level of 9 nmol/liter. The intraassay coefficient of variation was 5% at a 17-OHP level of 20 nmol/liter.
Basal levels. In addition, cortisol and cortisone levels were determined by applying extraction and chromatographic purification before RIA, as described previously (10). The detection limit with this method was 5 nmol/liter for cortisol and 1.3 nmol/liter for cortisone. With this technique the intra- and interassay coefficients of variation were 5% and 8%, respectively, for cortisol at a level of 0.27 µmol/liter and 6% and 11%, respectively, for cortisone at a level of 48 nmol/liter.
Statistical analysis
Results are presented as the mean ± SEM unless indicated otherwise. The baseline level was defined as the concentration at 0 min. Group differences were analyzed with ANOVA, Kruskal-Wallis H test, and 
2 tests when appropriate. For related samples, within-group differences between different time points and differences between the groups were analyzed with repeated measures analysis of covariance, followed by post-hoc analysis. Measures were adjusted for gestational age because adrenal steroidogenesis is dependent on gestational age (5). Significance was assumed when the probability value exceeded 95% (P < 0.05).
Results
BW were transformed to SD scores adjusted for gestational age, gender, and parity according to Dutch reference standards and were used as a measure of intrauterine growth (11). Results were analyzed with BW-SDS as a continuous variable, but also divided into three groups based on the range in BW-SDS (-2.5 to 0.5): group A (n = 10): BW-SDS, -2.5 to -1.5; group B (n = 17): BW-SDS, -1.5 to -0.5; and group C (n = 16): BW-SDS, -0.5 to 0.5. No significant differences were found between the groups in the levels of arterial cord blood pH, and SNAP, indicating comparable levels of initial severity of disease. However, preterm infants with the lowest BW-SDS stayed in our intensive care unit for a longer period, required supplemental oxygen for a longer time, had a higher incidence of chronic lung disease at 28 d and required parental feeding over a longer period (Table 1
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Cortisol response
The independent overall effect of gestation and BW-SDS on the cortisol response showed a trend toward higher cortisol values in preterm infants with a higher gestational age (P = 0.06) and in infants with the highest BW-SDS (P = 0.06). Figure 1 shows the results of basal and stimulated levels of cortisol in the different BW-SDS groups. Cortisol levels increased significantly after stimulation compared with baseline in all groups (P < 0.001). Cortisol levels were significantly lower in group A compared with group C after 30 min (P < 0.05; 395 ± 49 vs. 539 ± 39 nmol/liter) and 60 min (P < 0.05; 488 ± 73 vs. 719 ± 58 nmol/liter), but not at baseline (P = 0.18; 185 ± 39 vs. 261 ± 31 nmol/liter). Levels of cortisol in group B were intermediate (baseline, 189 ± 30; 30 min, 474 ± 38; 60 min, 602 ± 56 nmol/liter) and were not significantly different from either group A or C.
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The overall effect of gestation (P < 0.01) and BW-SDS (P < 0.02) on the 17-OHP response was significant. Figure 2 shows the basal and stimulated levels of 17-OHP. Levels of 17-OHP increased significantly after stimulation compared with baseline in all groups (P < 0.05). Levels of 17-OHP were significantly lower in group A compared with group C at all time points studied (P < 0.05; baseline, 54 ± 15 vs. 106 ± 12; 30 min, 61 ± 18 vs. 118 ± 14; 60 min, 67 ± 18 vs.123 ± 14 nmol/liter). Levels of 17-OHP in group B were intermediate (baseline, 65 ± 11; 30 min, 82 ± 13; 60 min, 93 ± 13 nmol/liter) and not significantly different from group A or C.
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The ratio between cortisol and 17-OHP is used as an indirect measure of adrenal cortex maturity because it reflects the activity of important adrenal cortex enzymes such as 21-hydroxylase (5). No significant overall effect was found for BW-SDS on the cortisol/17-OHP ratio adjusted for gestational age (P = 0.84). The cortisol/17-OHP ratio increased in group A from 3.6 ± 0.8 at baseline to 6.5 ± 1.2 and 7.5 ± 1.3 after 30 and 60 min, respectively (P = 0.01). In group B cortisol/17-OHP increased from 3.4 ± 0.6 to 7.2 ± 0.9 after 30 and 8.0 ± 1.0 after 60 min of stimulation (P = 0.02). The cortisol/17-OHP ratio in group C increased from 3.1 ± 0.6 to 5.9 ± 0.9 and 7.7 ± 1.1 (P = 0.03). No significant differences were found between the different BW-SDS groups at baseline (P = 0.87) or after stimulation (30 min, P = 0.56; 60 min, P = 0.94).
Basal levels of cortisone and cortisol
An overall effect of BW-SDS on the basal levels of cortisone was found (P < 0.04), but this was not the case for the basal levels of cortisol (P = 0.79) and the cortisol/cortisone ratio (P = 0.25) in the studied preterm infants. Basal levels of cortisone differed between the BW-SDS groups (P < 0.05), with the highest cortisone levels in group A: group A, 129 ± 14 nmol/liter; group B, 87 ± 10 nmol/liter; group C, 90 ± 11 nmol/liter. The basal levels of cortisol and the cortisol/cortisone ratio did not differ between the BW-SDS groups (P = 0.90 and P = 0.48, respectively): group A: cortisol, 0.09 ± 0.03 µmol/liter; ratio, 0.73 ± 0.56; group B: cortisol, 0.08 ± 0.02 µmol/liter; ratio, 1.00 ± 0.43; and group C: cortisol, 0.10 ± 0.02 µmol/liter; ratio, 1.54 ± 0.44.
Effect of clinical characteristics on the adrenal response to ACTH
Only five preterm infants (group B, n = 2; group C, n = 3) did not receive ANS (Table 1). The area under the curve for cortisol did not differ between infants who received ANS and those who did not (495 ± 85 vs. 442 ± 26; P = 0.45). Furthermore, after exclusion of infants who did not receive ANS, the levels of cortisol remained significantly different between group A and group C at 30 min (388 ± 51 vs. 524 ± 44 nmol/liter; P < 0.05) and 60 min (476 ± 65 vs. 697 ± 62 nmol/liter; P < 0.03) after stimulation.
No correlations were found between the cortisol increase and the SNAP (r = -0.06; P = 0.68), the number of days of mechanical ventilation (r = -0.24; P = 0.14), the number of days of supplemental oxygen (r = -0.18; P = 0.28), and the number of days of total parental nutrition (r = -0.04; P = 0.82). However, the cortisol increase showed a trend to be higher in infants with the shortest hospital stay (r = -0.30; P = 0.07).
The cortisol increase in infants receiving continuous positive airway pressure during the ACTH test (n = 4; 511 ± 175 nmol/liter) did not differ from that in infants receiving mechanical ventilation (n = 39: 400 ± 29 nmol/liter). Excluding these infants from the analysis did not change the results (effect of BWSDS and gestation on the cortisol response, P = 0.05 and P = 0.06, respectively)
Discussion
In the present study we show that the adrenocortical response to ACTH stimulation in preterm infants is related to fetal growth, i.e. infants with the lowest birth weight SD scores have the lowest cortisol response during the early neonatal period. The levels of 17-OHP are also lower before and after ACTH stimulation in preterm infants with inhibited fetal growth. These findings suggest that in utero growth-restricted preterm infants have a lower steroidogenic capacity than preterm infants with uninhibited fetal growth. This concept is consistent with earlier findings by others that hypoglycemia-induced and birth-associated stress do not adequately elevate cortisol levels in intrauterine growth retarded (IUGR) infants during the first 15 d of life (12, 13).
Preterm infants who are growth restricted in utero have increased rates of mortality and morbidity after birth, and the risk of adverse outcomes increases with a decreasing birth weight percentile (1, 2). Respiratory distress and subsequent chronic lung disease of prematurity, cardiovascular instability, and/or neurological complications remain the most important determinants of increased neonatal morbidity among preterm infants. Recently, several investigators have suggested that the adrenal cortex may be important in neonatal morbidity in preterm infants (3, 4). A low secretory capacity of the adrenal cortex may cause a diminished stress response during acute illness in preterm infants, which could lead to increased morbidity in these infants.
We suggest that not only prematurity is associated with an insufficient response to stress, but fetal growth restriction by itself may contribute to a higher neonatal morbidity in these infants due to a lower steroidogenic capacity of the adrenal cortex (3, 5). Indeed, the infants with the lowest birth weight SD score were admitted to our intensive care unit for a longer time, required supplemental oxygen for a longer period, had a higher incidence of chronic lung disease, and required parenteral feeding longer, as found by others (1, 2). Although no direct relations were found between clinical outcome and the cortisol response, we did find a trend toward a longer length of hospital stay in infants with the lowest cortisol response.
Several factors have been implicated as important in the adrenal response to stimulation in preterm infants. ANS administered to mothers at risk of preterm birth may suppress the hypothyroid-pituitary-adrenal axis (HPAA) in preterm infants directly after birth, but not after the first week of life (14). With regard to the small number of mothers (11.6%) not treated with antenatal glucocorticoids, our study does not provide information on the suppressive or nonsuppressive effect of ANS on postnatal adrenal function in preterm infants. However, exclusion of preterm infants who were not treated with antenatal glucocorticoids did not alter the results. In addition, the infants were tested between the 5th and 12th postnatal day, and we did not found an effect of postnatal age on the adrenal response (data not shown). It has been shown that the severity of disease and mechanical ventilation may affect the adrenal response to ACTH stimulation (4). However, our present study did not support these findings. A possible explanation for the lack of effect of mechanical ventilation and severity of disease on the adrenal response is the fact that our preterm infants were all respiratory insufficient, had respiratory support, and were at risk of developing chronic lung disease of prematurity. Furthermore, our groups were comparable for severity of disease (and clinically stable) at the time of the ACTH test.
It has been suggested that a diminished capacity to produce cortisol in growth-retarded infants may be related to enzyme deficiencies in the adrenal cortex (13, 15, 16). Recently, Van der Kamp et al. (17) have also shown that in preterm infants the basal level of 17-OHP is better related to gestational age than birth weight. In the present study we found no such a relations (data not shown); however, this may be caused by the small number of infants and the small range of gestational ages. We were unable to show differences in the ratio between cortisol and the cortisol precursor, 17-OHP, adjusted for gestational age, which indicates that fetal age, not fetal growth, is important in the maturity of adrenal cortex enzymes (5). The ratio between cortisol and 17-OHP does not test all adrenal cortex enzymes, only 21-hydroxylase and 11ß-hydroxylase. In addition, the ratio between cortisone and cortisol in a basal blood sample was not related to fetal growth. This indicates that fetal growth does not influence the activity of 11ßHSD in preterm infants during the first week of life. We choose to determine only these hormones, because blood sampling is limited in preterm infants, and our aim was to study the last step of glucocorticoid production, because this is related to pulmonary development (3). Several other researchers have already shown that the fetal adrenal cortex is relatively deficient in 3ßHSD, which results in high levels of dehydroepiandrosterone in preterm infants (18, 19).
Basal levels of cortisol did not appear to be related to intrauterine growth. Contradictory observations have been made regarding nonstimulated levels of glucocorticoids in IUGR infants. Some investigators observed lower levels of cortisol, whereas others observed comparable or even higher levels during the early neonatal period in SGA infants compared with AGA infants (13, 16, 20, 21, 22). Basal cortisol levels are influenced by many factors, including gestational age and severity of disease (22), and therefore do not appropriately reflect the ability of the adrenal cortex to secrete glucocorticoids.
Although the present study does show lower adrenal responses to stimulation in IUGR infants, the exact mechanisms are unknown. However, several mechanisms may be responsible for this observation. First, the adrenal cortex in growth-restricted fetuses is deprived of nutrients in utero, which may directly alter the growth and function of the adrenal cortex and therefore leads to a lower steroidogenic capacity. This explanation is supported by the observation that growth-restricted fetuses have a disproportionately small adrenal cortex and fetal zone (23).
Besides a direct effect of deprived nutrients on adrenal growth in growth-restricted fetuses, an alternative explanation may be that inhibition of fetal growth in utero indirectly leads to changes in the HPAA. This concept is known as reprogramming and is part of the fetal origin of adult disease hypothesis proposed by Barker et al. (24). It is speculated that an insult during a sensitive period of development may cause a change in programming and exert organizational effects on fetal structures that permanently alter regulatory systems (25). Strong associations between low birth weight and the occurrence of hypertension, insulin resistance, noninsulin-dependent diabetes mellitus, and ischemic heart disease in later life suggest that these alterations of regulatory systems exist in IUGR infants (24, 26). Preterm infants who complete their growth outside the uterus are at risk of impaired postnatal growth, which may have the same consequence of increased cardiovascular risk as impaired fetal growth in term infants. Irving et al. (27) recently found that preterm infants indeed have an increased risk of cardiovascular disease in later life.
Besides a possible direct and indirect effect of shortage of nutrients, several investigators have proposed that increased fetal glucocorticoid exposure may cause growth inhibition and reprogramming and may therefore be involved in the fetal origins of adult disease hypothesis (25, 28). Edwards et al. (28) hypothesized that a relative deficiency of placental 11ßHSD-2 causes an increased transfer of maternal glucocorticoids to the fetus that retards growth. In rats and humans low activity of placental 11ßHSD-2 is associated with small fetal size and the development of cardiovascular sequalae (25, 29, 30). However, the development of the hypothalamus and other brain structures may also be influenced by lower levels of insulin in growth-retarded fetuses (26, 31).
IUGR fetuses indeed show increased levels of cortisol in umbilical cord blood combined with a smaller adrenal cortex (32, 33). Furthermore, in utero levels of cortisol are high in growth-retarded fetuses, whereas ACTH levels are low (31, 34, 35). With respect to the concept of Edwards et al. (28), the combination of high cortisol and low ACTH levels in growth-restricted fetuses may be caused by an increased transfer of glucocorticoids through the placenta.
Based on these findings, we hypothesize that not only inhibition of fetal growth by deprived nutrients, but also high levels of glucocorticoids in the fetus may inhibit the growth of the adrenal cortex directly or indirectly by influencing the regulation of the HPAA in utero. This may also alter the sensitivity of the adrenal cortex upon stimulation to secrete glucocorticoids after birth.
Taken together, these findings may be integrated into the following concept. In the growing fetus growth and function of the adrenal cortex may be directly influenced by available nutrients and/or indirectly by reprogramming of the HPAA. In addition, a low activity of 11ßHSD in the placenta of IUGR infants may increase placental transfer of glucocorticoids and directly and/or indirectly influence the growth and function of the adrenal cortex as well.
The lower adrenocortical response to stimulation in preterm infants with fetal growth inhibition may indicate an insufficient response to stress in such a way that it may contributes to higher rates of morbidity and mortality. The results of the present study, i.e. the adrenal response to ACTH stimulation, cannot differentiate between adrenal and pituitary causes of a diminished response. Further studies of the development of the hypothalamic-pituitary adrenal axis in (ex-)preterm infants should be encouraged to provide information about the relation between intrauterine development and neonatal disease as well as disease in later life.
Acknowledgments
Footnotes
Abbreviations: AGA, Appropriate for gestational age; ANS, antenatal steroids; BW, birth weight; BW-SDS, birth weight SD score; HPAA, hypothalamic-pituitary-adrenal axis; 11ßHSD, 11ß-hydroxysteroid dehydrogenase; IUGR, intrauterine growth retarded; 17-OHP, 17- hydroxyprogesterone; SGA, small for gestational age; SNAP, score for neonatal acute physiology.
Received April 16, 2001.
Accepted November 27, 2001.
References
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