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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0870
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5737-5742
Copyright © 2005 by The Endocrine Society

Cortisol Production Rates in Preterm Infants in Relation to Growth and Illness: A Noninvasive Prospective Study Using Gas Chromatography-Mass Spectrometry

Matthias Heckmann, Michaela F. Hartmann, Birgit Kampschulte, Heike Gack, Rolf-Hasso Bödeker, Ludwig Gortner and Stefan A. Wudy

Department of General Pediatrics and Neonatology (M.H., B.K., H.G., S.A.W.), Steroid Research Unit (M.F.H., S.A.W.), and Institute of Medical Statistics (R.-H.B.), Justus Liebig University, 35385 Giessen, Germany; and Department of General Pediatrics and Neonatology (L.G.), University of Saarland, 66421 Homburg/Saar, Germany

Address all correspondence and requests for reprints to: Matthias Heckmann, M.D., Department of General Pediatrics and Neonatology, Justus Liebig University, 35385 Giessen, Germany. E-mail: Matthias.Heckmann{at}paediat.med.uni-giessen.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Whereas intrauterine growth and maturation depend on low cortisol levels, an adrenal stress response postnatally is thought to be mandatory in preterm infants.

Objective: The goal of this study was to determine cortisol production rates (CPRs) in preterm infants during early life with extreme illness and, thereafter, during extrauterine growth and maturation.

Design: We describe a longitudinal observational study.

Setting: The study was conducted at a university neonatal intensive care unit.

Patients and Methods: Seventeen well (27.9 ± 1.8 wk) and 44 ill (27.3 ± 1.6 wk) preterm infants were classified by the Score for Neonatal Acute Physiology. Glucocorticoid metabolites were profiled by gas chromatography-mass spectrometry in 24-h urinary samples. Urine was collected noninvasively using cellulose nappies and extracted by hydraulic press.

Results: Medians of CPRs (µg kg–1d–1mg creatinine) in ill (well) preterm infants were as follows: at d 1, 35 (40); d 2, 35 (40); d 3, 48 (53); d 5, 47 (41); wk 2, 72 (48); wk 3, 73 (37); wk 4, 54 (26). Regression analysis revealed a significant inverse influence of gestational age (P < 0.005) on the maximum of CPRs but not of severity of illness (Score for Neonatal Acute Physiology; P = 0.72). A mature adrenal response was found in only 12 of 44 (27%) ill preterm infants, who had CPRs higher than the 3-fold median of CPRs of well infants. This mature adrenal response was associated with a significantly higher incidence of cerebral bleeding: 9 of 12 (75%) vs. 8 of 32 (25%) without such a response (P = 0.003). During growth, CPRs of ill (well) preterm infants decreased: at month 2, 30 (18); month 3, 18 (22); correlation between weight gain and decrease of CPRs in ill infants between wk 4 and month 3, r = –0.48 (P = 0.027).

Conclusions: Severity of illness did not have a significant influence on CPRs in preterm infants. However, the highest CPRs were associated with a significantly higher incidence of cerebral bleeding. During growth, CPRs decreased significantly, suggesting that preterm infants have the ability to regulate cortisol production. CPRs in ill preterm infants might reflect inadequate stress reaction, but this could also reveal persistence of fetal protective mechanisms against high catabolic cortisol concentrations.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CONCERNING THE FUNCTION of the hypothalamic-pituitary-adrenal axis (HPAA), preterm birth starts with a dilemma. The premature infant has to counterbalance the hormonal demands of acute critical stress against those of growth and organ maturation. On the one hand, severe illness, due to immature organs, demands a stress response from the immature HPAA. A fetus of 20 wk gestational age was found to be able to respond to painful invasive stimuli with a rise in plasma cortisol (1). It was shown that the magnitude of adrenal stress response matures over months with gestational age (1). This process is far from being completed when a preterm infant of 24 wk gestational age is admitted to an intensive care unit. On the other hand, an important function of fetal cortisol is to promote maturation of fetal organ systems (2). For this purpose, fetal cortisol levels are low and strictly regulated by the placental enzyme 11ß-hydroxysteroid-dehydrogenase type 2, presumably to protect the fetus against high active glucocorticoid levels (3, 4). Data from animal studies showed that fetal exposure to high glucocorticoid levels leads to an impairment of fetal growth and organ maturation (5, 6, 7). However, a mature adrenal stress response consisted of an increase in plasma cortisol levels by as much as a factor of six during severe infection, illness, or surgery (8).

Until now, studies on adrenal function in the immediate postnatal period have comprised the measurement of random plasma cortisol levels and pharmacological tests of the HPAA. Plasma cortisol levels were found to be inappropriately low during acute pulmonary and circulatory illness (9, 10, 11, 12). Although basal cortisol levels were found to be low, a normal response to ACTH and CRH was found. Other groups reported an attenuated response to the ACTH test in ventilated preterm infants (13, 14, 15). However, it is clear that measurement of a single random plasma cortisol concentration provides information about only an instant time, whereas the measurement of daily urinary total glucocorticoid excretion has the advantage of providing an integrated index of cortisol production (16, 17). It was shown that determination of total glucocorticoid metabolites in 24-h urinary specimens reflects 75% of the cortisol production rate (CPR) in adults (17). We have recently reported on a noninvasive method to reliably assess CPRs in premature infants (18). The urine collection is performed by using disposable pure cellulose nappies, from which the urine is recovered by hydraulic compression. Urinary glucocorticoid metabolites are then profiled by quantitative gas chromatography-mass spectrometry (GC-MS). Applying this method, urinary excretion rates of glucocorticoids in preterm infants constitute approximately 70% of the natural cortisol production rate, as determined by stable isotope dilution technique in older children (19) or adults (17, 20).

The aim of this prospective study was 2-fold: first, to determine CPRs in preterm infants during the early neonatal period with high illness severity; and second, to determine CPRs longitudinally during extrauterine growth and maturation until discharge.

On the basis of the current knowledge (21), we hypothesized that CPRs will not increase adequately in severely ill preterm infants compared with clinically well preterm infants.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The study was approved by the Ethics Committee of the Justus Liebig University of Giessen, and written informed parental consent was obtained.

Patients

Only preterm infants with a gestational age of less than 30 wk, who had no family history of adrenal illnesses and who had no major congenital anomalies, were eligible for the study. A postnatal steroid therapy was a criterion for exclusion. Gestational age was determined using the expanded Ballard score and/or obstetrical dating. Small for gestational age was defined as a birth weight less than the 10th percentile. A prenatal betamethasone therapy was recorded as being complete if two doses of 12 mg betamethasone were given to the mother more than 24 h ante partum.

Preterm infants were classified as being well according to our recently described criteria (22). Well infants had no signs of infection and did not receive treatment with surfactant or inotropes. Ill preterm infants suffered from one or more of the following diseases: respiratory-distress syndrome treated with surfactant (23), infection at birth (C-reactive protein >10 mg/liter and symptoms of an infection during the first 72 h of life), hospital infection (C-reactive protein >10 mg/liter and symptoms of an infection after the first 72 h of life), ventricular hemorrhage more than II° according to the criteria of Papile et al. (24). To assess the severity of illness, all infants were scored using the Score for Neonatal Acute Physiology (SNAP) on each day when CPRs were determined (12, 25).

Urine-collection procedure

Twenty-four-hour urine collections were made frequently in the first week of life, i.e. on the first, second, third, and fifth day of life, because severity of illness was expected to be highest in this period. Thereafter, 24-h urine collections were made at weekly intervals during the first month of life and then monthly up to discharge. The urine-collection procedure has been described recently (18). In brief, urine was collected for 24 h using disposable nappies composed of pure cellulose (Pampers; Procter & Gamble, Schwalbach, Germany). Weighing the nappies before and after urine collections allowed exact calculation of 24-h urine output. Urine was extracted by compressing the nappies using a hydraulic press applying a maximum of 120 kPa/cm2. After centrifugation, the collected urinary specimens were stored at –80 C until analysis by GC-MS.

Laboratory analyses

Urinary steroid profiles were determined by GC-MS analysis according to our procedure described recently (18). The following C21-steroids/cortisol metabolites were determined by selected ion monitoring: tetrahydrocortisone (THE) (5ß-pregnan-3{alpha},17{alpha},21-triol-11,20-dione); {alpha}-cortolone ({alpha}-CL) (5ß-pregnan-3{alpha},17{alpha},20{alpha},21-tetrol-11-one); ß-CL (5ß-pregnan-3{alpha},17{alpha},20ß,21-tetrol-11-one); 6{alpha}-OH-THE (5ß-pregnan-3{alpha},6{alpha},17{alpha},21-tetrol-11,20-dione); 1ß-OH-THE (5ß-pregnan-1ß,3{alpha},17{alpha},21-tretrol-11,20-dione); 6{alpha}-OH-{alpha}-CL (5ß-pregnan-3{alpha},6{alpha},17{alpha},20{alpha},21-pentol-11-one); 6{alpha}-OH-ß-CL (5ß-pregnan-3{alpha},6{alpha},17{alpha},20ß,21-pentol-11-one); 1ß-OH-ß-CL (5ß-pregnan-1ß,3{alpha},17{alpha},20ß,21-pentol-11-one); tetrahydrocortisol (5ß-pregnan-3{alpha},11ß,17{alpha},21-tetrol-20-one); allotetrahydrocortisol (5{alpha}-pregnan-3{alpha},11ß,17{alpha},21-tetrol-20-one); {alpha}-cortol (5ß-pregnan-3{alpha},11ß,17{alpha},20{alpha},21-pentol); ß-cortol (5ß-pregnan-3{alpha},11ß,17{alpha},20ß,21-pentol); cortisol (4-pregnene-11ß,17{alpha},21-triol-3,20-dione); 6ß-OH-cortisol (6ß-OH-F; 4-pregnene-6ß,11ß,17{alpha},21-tetrol-3,20-dione).

To assess overall cortisol secretion, these 14 major urinary glucocorticoid metabolites were quantified (peak-area integration) and summed. Daily urinary excretion rates of glucocorticoids were corrected for body weight per micromoles creatinine to take into account changes in glomerular filtration rate especially during the first week of life (18).

Statistics

All data were analyzed in the Institute of Medical Statistics using the SAS version 8 statistical package (SAS Institute, Inc., Cary, NC). Preterm infants were separated into two groups based on their classification of being well or ill. All intergroup differences were compared with the Mann-Whitney U test for continuous variables and the Fisher’s exact test for categorical data. Logistic regression analysis was used to investigate the effect of the severity of illness measured by SNAP and covariables on the maximum CPR. Spearman rank analysis was used to analyze the decrease of CPRs during growth. We considered P < 0.05 as significant. Multiple comparisons were made; thus, isolated significant differences should be taken as provisional.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patients

Sixty-seven preterm infants with a gestational age of less than 30 wk were admitted to our neonatal unit between July 2001 and September 2002. Sixty-one of them matched the study criteria. Reasons for exclusion were postnatal steroid therapy (n = 5) and chromosomal aberration (trisomy 21, n = 1). Table 1Go shows the characteristics of well (n = 17) and ill (n = 44) preterm infants. As anticipated from the definition of allocation to the groups, the incidences of common neonatal complications were high in the group of ill preterm infants: respiratory-distress syndrome treated with surfactant, 35 (80%); intraventricular hemorrhage more than II°, 7 (16%); infection at birth, 20 (45%); and hospital infection, 27 (61%). However, only five (11%) of the ill preterm infants had severe potential signs of adrenal insufficiency in terms of arterial hypotension, which required treatment with catecholamines. Two (12%) infants of the control group and 21 (48%) of the ill preterm infants developed bronchopulmonary dysplasia (fraction of inspired oxygen, >0.21 at the 28th day); however, none of the infants required supplemental oxygen at 36 wk. Five (11%) infants of the ill infants died before discharge. The distribution of potential confounding variables (gestational age, gender, administration of prenatal steroids, and mode of delivery) were similar in well and ill preterm infants (Table 1Go).


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  		TABLE 1. Distribution of population characteristics of well and ill preterm infants

 
Influence of severity of illness on cortisol production

SNAPs were significantly higher in ill preterm infants compared with control infants throughout the neonatal period, i.e. the first 4 wk of life, with the highest severity of illness measured in wk 1 (Fig. 1BGo). There seemed to be a rise in urinary CPRs corrected for creatinine excretion after wk 1 (Fig. 1AGo). Therefore, we looked at the distribution of maxima of SNAP and CPRs over time (Fig. 2Go). Compared with Fig. 1Go, the inverse pattern of SNAP and CPRs became more distinct. Assuming a delayed adrenal response during severe illness in the neonatal period, and to take the individual stress response of each infant into account, we tried to describe the adrenal response in a model using logistic regression analysis. Table 2Go summarizes the results of the analysis, in which the maximum of CPRs corrected for creatinine excretion dichotomized at the median served as the dependent variable. Only gestational age as a covariable showed a significant inverse relationship to the maximum of CPRs, but the severity of illness was not a significant factor. Additional analyses including the same covariables did not show any influence of severity of illness measured by SNAP neither on magnitude of the increase of CPRs (difference between minimum and maximum CPR; P = 0.84) nor on the ascending slope of the increase of CPRs (P = 0.48).



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  		FIG. 1. Changes in urinary CPRs corrected for urinary creatinine excretion (A), severity of illness quantified by SNAP (B), and body weight (C) in well ({blacksquare}) and ill ({square}) preterm infants less than 30 wk gestational age as a function of postnatal age (median and interquartile range).

 


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  		FIG. 2. Distribution of maxima of SNAP and maxima of CPRs in preterm infants of less than 30 wk gestational age in the first month of life.

 

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  		TABLE 2. Nonparametric logistic regression analysis of the effects of different variables on the maximum of cortisol production rate corrected for creatinine excretion dichotomized at the median in preterm infants in the first 4 wk of life

 
Even if we found no differences in CPR between well and ill preterm infants, it was apparent that CPR showed a wide variation. The different adrenal responses of two severely ill preterm infants are shown in Fig. 3Go. Although both infants had comparably high SNAP, their adrenal response was strikingly different. To analyze whether ill preterm infants benefit from a high CPR, a mature type of adrenal response to severe illness was defined. Ill infants were allocated to have a mature adrenal response when their CPR exceeded the 3-fold mean of the medians of CPRs of well infants during the period of highest SNAP, i.e. the first week of life. We chose the 3-fold median of CPR of well preterm infants for our subgroup analysis because it is recommended in pediatric intensive care to choose at least 25 mg m–2 hydrocortisone to treat patients with adrenal crisis. This recommended dosage is about three times the nonstressed physiological daily dose of 8 mg m–2. Table 3Go summarizes the results. These infants with a mature adrenal response [12 (27%) of 44 ill infants] had a significantly higher incidence of ventricular hemorrhage and tended to be of lower gestational age compared with infants with a lower adrenal response.



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  		FIG. 3. CPRs corrected for urinary creatinine excretion and severity of illness quantified by SNAP in two different severely ill preterm infants.

 

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  		TABLE 3. Comparison of clinical variables between ill preterm infants whose CPRs increased above the 3-fold median of CPRs of well infants and those whose CPRs remained below the 3-fold median

 
Because phenobarbital is known to be an activator of glucocorticoid catabolism and fentanyl is known to attenuate the adrenal stress response (26, 27), the administration of these drugs was recorded. Differences in the administration of these drugs were not found between ill preterm infants with high and low CPRs.

Longitudinal pattern of cortisol production

After the neonatal period, CPRs decreased during the following postnatal course when the preterm infants started to gain weight (Fig. 1CGo). For example, there was a significant negative correlation between weight gain and the decrease of CPRs in ill infants between wk 4 and month 3 (r = –0.48; P = 0.027).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Using an integral parameter of adrenal glucocorticoid secretion, we were able to demonstrate that, in preterm infants, the adrenal response to stress does not correspond to the pattern of adult patients (8). However, the median (interquartile range) of CPR of our entire population of preterm infants were 2.6 (1.9–4.8), 4.1 (2.4–5.5), 4.4 (3.4–6.4), and 3.7 (2.8–4.9) mg m–2 d–1 at the fifth day and at the second, third, and fourth week, respectively. These data confirmed our recent reported results (18) that renal glucocorticoid excretion rates, which were determined noninvasively in preterm infants during the first 4 wk of life, approach the basal CPR of children (19) and adults (17, 20). These findings are in accordance with in vivo studies in the fetal rhesus monkey, which showed that the fetal rhesus adrenal secreted cortisol at rates equaling or exceeding those of the adult rhesus monkey (28, 29).

However, human fetal plasma cortisol levels were reported to be low, ranging from 20–50 nmol liter–1 (1, 30), due to rapid metabolic clearance by inactivation to cortisone via 11-ß-hydroxysteroid-dehydrogenase type 2 (3). We and others found postnatal plasma cortisol levels in preterm infants to be 5–10 times higher than the fetal levels at the same gestational age (11, 12, 31). Considering the fetus as the control group, preterm infants are able to increase plasma cortisol levels. However, no rise of CPRs was found in ill preterm infants when well infants were chosen as the control group.

The poor adrenal response to critical illness in preterm infants may be based on two issues: the concept of relative adrenal insufficiency known from the adult critical care patient (26) and the immature HPAA. Patients with a so-called relative adrenal insufficiency have plasma cortisol values that might be considered normal for well individuals but are inappropriately low for their degree of illness. In adult patients with septic shock, the incidence of relative adrenal insufficiency (diagnosed by the CRH test) was high (70%), the outcome was worse, and hydrocortisone therapy (200 mg d–1) was found to be beneficial for them (32, 33). The immature HPAA comprises two hypotheses: 1) a reduced capacity to produce cortisol due to deficiency of 3ß-hydroxysteroid dehydrogenase or 2) the attempt to protect itself against excessive levels of cortisol in terms of postnatal persistence of some of the fetal mechanisms to regulate glucocorticoid homeostasis. The observation from the literature that maturation of the adrenal stress response continued with gestational age underlines the first hypothesis (1). The second hypothesis may be supported by the results of our study. At first, high CPRs were associated with a significantly higher rate of cerebral bleeding but no benefit. Additionally, the patient with very low CPRs in the face of high SNAP survived without a major handicap (Fig. 3Go). Secondly, our longitudinal data also support the second hypothesis because CPR declined after the immediate postnatal period when the preterm infants started to gain weight. This suggests that the preterm infant is able to down-regulate this catabolic hormone during growth.

Thus, concerning the function of the immature HPAA, the neonatologist has a therapeutical dilemma. Should ill preterm infants receive a replacement therapy with hydrocortisone? In contrast to the infants investigated in our study, more immature infants with birth weights less than 1000 g were included in a pilot study of low-dose hydrocortisone therapy to prevent chronic lung disease (34). Although this small study could demonstrate a beneficial effect, two recently reported multicenter trials failed to show a reduction of chronic lung disease (35, 36). In both studies, hydrocortisone was administered at a dose of 1 mg/kg, which should approach basal cortisol production (34).

In conclusion, urinary CPR of preterm infants of less than 30 wk gestational age approach CPR of older children and adults. However, during critical illness, a rise of cortisol production was absent. Concerning severity of illness, CPR in ill preterm infants is blunted. This could reveal persistence of intrauterine mechanisms of cortisol regulation, possibly to protect the preterm infant against high glucocorticoid levels. Down-regulation of cortisol production, which was noted after the immediate neonatal period during growth until the day of discharge, may also be a part of this mechanism of protection against high catabolic cortisol concentrations. Glucocorticoid therapy in preterm infants should be limited to well-controlled randomized trials, which comprise short (incidence of severe hypotension), medium (incidence of bronchopulmonary dysplasia), and long-term effects (neurological outcome). Before completion of such trials and in face of the adverse effects of postnatal steroids in preterm infants (37), the question arises whether the absence of a postnatal adrenal stress response may be protective in preterm infants of less than 30 wk gestational age.


   Acknowledgments
 
We thank M. Lazaro, M.D., for proofreading the manuscript and Procter & Gamble for manufacturing the medium-sized nappies.


   Footnotes
 
This work was supported by a grant of the Deutsche Forschungsgemeinschaft to M.H. and S.A.W. (HE 3557/1-1).

First Published Online July 19, 2005

Abbreviations: CL, Cortolone; CPR, cortisol production rate; GC-MS, gas chromatography-mass spectrometry; HPAA, hypothalamic-pituitary-adrenal axis; SNAP, score for neonatal acute physiology; THE, tetrahydrocortisone.

Received April 20, 2005.

Accepted July 11, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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