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Pituitary-Adrenal Response in Preterm Very Low Birth Weight Infants after Treatment with Antenatal Corticosteroids

Departments of Pediatrics (P.C.N., G.W.K.W., C.H.L., T.F.F., W.W.) and Chemical Pathology (C.W.K.L., D.C.F.C.), Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong; and the Department of Mathematics (M.Y.W.), The Hong Kong University of Science and Technology, Hong Kong

Address all correspondence and requests for reprints to: P.C. Ng, Associate Professor in Pediatrics and Honorary Consultant Neonatologist, Department of Pediatrics, Level 6, Clinical Sciences Building, Princes of Wales Hospital, Shatin, N.T., Hong Kong.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Antenatal corticosteroids have been widely used for the prevention of respiratory distress syndrome in preterm neonates, yet little is known about their effects on the hypothalamic-pituitary-adrenal axis in these infants. We prospectively evaluated pituitary-adrenal function in 61 preterm (<32 gestational weeks), very low birth weight (<1500 g) infants on days 7 and 14 of life using the human CRH stimulation test.

The baseline and poststimulation plasma ACTH and serum cortisol concentrations did not differ significantly between infants whose mothers received no antenatal corticosteroids, and those whose mothers received 1–2 doses or >2 doses (mean 7.2 doses) of prenatal dexamethasone (P = > 0.12). The number of doses of dexamethasone and the time intervals between the last dose of drug and delivery did not significantly affect the pituitary-adrenal responsiveness on days 7 and 14 of life. Among infants who did not require mechanical ventilation at the time of the human CRH test, significantly higher plasma ACTH (P < 0.014) and lower serum cortisol concentrations (P < 0.02) were found on day 14 than on day 7. In contrast, none of the poststimulation hormone concentrations were significantly different in ventilated infants between days 7 and 14.

The relationship between the blood hormone concentrations in each time epoch (day 7 and day 14) and possible confounding factors including gestational and postconceptional age, birth weight, sex, Apgar scores, mode of delivery, single or higher order births, and mode of ventilation were determined. Plasma ACTH concentrations on day 7 were found to be significantly higher in ventilated than in nonventilated infants (P = 0.006). However, none of the aforementioned factors correlated significantly with plasma ACTH concentrations on day 14. Serum cortisol concentrations on day 7 were significantly higher in infants of greater gestational age (P = 0.039) and birth weight (P = 0.013), with lower Apgar scores at 1 and 5 min (P = 0.021 and P = 0.049, respectively), and in those delivered vaginally (P = 0.047). Similarly, serum cortisol concentrations on day 14 were found to be significantly higher in infants with lower Apgar scores at 1 and 5 min (P = 0.011 and P = 0.014, respectively) and in infants requiring mechanical ventilation (P = 0.014).

Our results suggest that single or multiple courses of antenatal dexamethasone have no long-lasting suppressive effects on pituitary-adrenal function in preterm, very low birth weight infants. Maturation of pituitary function appears to be more advanced than adrenal function. The organ’s ability to respond appropriately to various stressful stimuli indicates that the pituitary-adrenal axis is highly responsive at these early gestational ages.

	Introduction

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THE DEVELOPMENTAL pathophysiology of lung maturation during the perinatal period has been the subject of fruitful research in the past decades (1). In many animal species, antenatal corticosteroids have been shown to stimulate cytodifferentiation and induce precocious acceleration of tissue maturation without altering the normal sequence of development (2). Much evidence has accumulated to show that antenatal corticosteroids do not only reduce the incidence and severity of respiratory distress syndrome (RDS) (3, 4), but could also decrease the incidence of bronchopulmonary dysplasia (5), intraventricular hemorrhage (6), necrotizing enterocolitis (7), and mortality in preterm infants (3, 4). Although the efficacy of antenatal corticosteroids for prevention of RDS is established and this treatment has become part of routine obstetric management in many institutions, there is relatively little information regarding its effects on the hypothalamic-pituitary-adrenal (HPA) axis and, in particular, the hypothalamic-pituitary centers of very low birth weight (VLBW) infants. To our knowledge, the pituitary function has not been systematically evaluated in this category of newborns. We set out to compare the pituitary-adrenal function in preterm, VLBW infants who did and did not receive antenatal corticosteroids treatment by prospectively examining their pituitary-adrenal function with the human CRH (hCRH) stimulation test in a standardized fashion. The influence of other confounding factors and stressful therapeutic measures on the HPA axis was also determined.

	Patients and Methods

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Study population

Sixty one preterm infants were prospectively enrolled between August 1994 and December 1996. Inclusion criteria were: 1) a gestation of less than 32 weeks and a birth weight below 1500 g; 2) presence of an indwelling arterial cannula at day 7 (a second hCRH test would also be performed if the arterial cannula was still in situ on day 14); and 3) no postnatal corticosteroids treatment. Gestational age assessment was by the mother’s last menstrual period, early ultrasound dating, and new Ballard Score examination (8). Infants were excluded if they had concurrent hypoglycemia, systemic infection, necrotizing enterocolitis, or major surgery in the preceding week.

Antenatal dexamethasone

The decision to administer antenatal dexamethasone rested entirely on the clinical judgment of the attending obstetrician. Management guidelines for starting antenatal dexamethasone therapy in women between 24–34 weeks gestation were: 1) threatened preterm labor; 2) antepartum hemorrhage; 3) preterm rupture of membranes; and 4) any condition requiring elective premature delivery. As the effect of antenatal corticosteroids wanes after 7 days (9), repeat courses were considered if the risk of imminent preterm delivery persisted or recurred following the initial treatment. Each course consisted of 2 doses of dexamethasone (dexamethasone sodium phosphate; Weimer Pharma, Gmbh, Rastatt, Germany) 10 mg given im 12 h apart.

hCRH stimulation test and hormone assays

We performed the hCRH stimulation test following a standard schedule on days 7 and 14, because we did not wish to disturb these ill preterm infants during their first few days of intensive care treatment, and to allow time for elimination of placental hormones from their circulation. Moreover, data from term infants suggested that the adrenal glands showed a relatively normal response to stimuli immediately after birth, followed by a blunted response over the next few days and full recovery of endocrine function towards the end of the first week of life (10). The hCRH stimulation test was performed between 0800–1000 h as previously described (11). The plasma ACTH and serum cortisol concentrations were measured by double-antibody RIA and solid-phase RIA, respectively (11).

Ethical approval

Ethical approval of the study was obtained from the Research Ethics Committee of the Chinese University of Hong Kong. Informed parental consent was obtained for each case before commencement of the test.

Statistical analysis

The descriptive statistics pertaining to demographic data included medians, means, and SEM. Multivariate ANOVA and unpaired Student’s t tests were used for comparing the hormone concentrations and for assessing the multiple correlation relationships between the hormone levels and the variables. All tests of significance used a two-tailed level of significance set at 0.05.

	Results

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The clinical characteristics of the study population are summarized in Table 1. One hundred and eight hCRH stimulation tests were performed in 61 VLBW infants at days 7 and 14 of postnatal age. Six infants missed the first hCRH test on day 7, of whom 4 were suspected to be septicemic and 2 did not possess an indwelling arterial cannula for blood sampling. Eight infants were not tested on day 14, of whom 3 died from respiratory failure before the age of 2 weeks, 2 developed fulminant necrotizing enterocolitis, and the remaining 3 infants were suspected to be infected. Twelve of the 17 infants who did not receive antenatal dexamethasone were described in our previous report concerning the methodology of performing hCRH test in preterm infants (11).

View larger version (23K): [in this window] [in a new window]   Figure 1. Effect of exogenous hCRH stimulation on plasma ACTH and serum cortisol concentrations in nonventilated VLBW infants at day 7 (n = 25) and day 14 of life (n = 30). Values are mean ± SEM.

View larger version (21K): [in this window] [in a new window]   Figure 2. Effect of exogenous hCRH stimulation on plasma ACTH and serum cortisol concentrations in ventilated VLBW infants at day 7 (n = 30) and day 14 of life (n = 23). Values are mean ± SEM.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Our results suggested that neither the number of dexamethasone doses nor the time intervals between the last dose of drug and delivery significantly affected the pituitary-adrenal responsiveness at days 7 and 14 of life. These findings were in line with previous observations that transient suppression of the adrenal glands because of antenatal corticosteroids would recover by the end of the first week (12, 13, 14). We also have shown that the pituitary’s ability to secrete ACTH was unaffected by antenatal corticosteroids. Although a blunted response of the HPA axis or adrenocortical degeneration at autopsy have been reported in newborns whose mothers received either multiple courses or continuous high-dose corticosteroids during pregnancy (15, 16), no demonstrable suppression of pituitary-adrenal responsiveness was found in our VLBW infants (n = 12) receiving >2 doses (mean = 7.2 doses, range 4–14 doses) of antenatal dexamethasone. However, the relatively small sample size in our study might not have adequate statistical power to detect small changes of ACTH or cortisol responses.

Gestational age and birth weight bore significant negative relationships only to serum cortisol concentrations on day 7, and no such association was found between these two parameters and plasma ACTH concentrations or serum cortisol concentrations on day 14. The findings suggested a continuing maturational process at the adrenal level with increasing gestational age and birth weight. However, by day 14, this maturational difference in adrenocortical response was no longer observed, possibly indicating gradual postnatal adaptation of the adrenal glands at this stage. The lack of significant association between gestational age and plasma ACTH concentrations at days 7 and 14 provided evidence that the pituitary gland was physiologically mature at these early gestational ages, and it was probably more advanced in development than the adrenals in preterm neonates.

Vaginal delivery, low Apgar scores, and mechanical ventilation were highly stressful experiences associated with significant increase in plasma ACTH or serum cortisol concentrations. The increase in cortisol secretion in vaginally delivered infants on day 7 was most likely the result of intense stress induced by parturition. Previous studies have shown an increase in the circulating cortisol concentration after active labor and vaginal delivery as opposed to cesarean section (17, 18, 19). This stress-related response was, however, transient as the mode of delivery did not appear to affect the resting or poststimulation cortisol secretion by day 14. The Apgar scores represent a measure of the initial clinical status of the infant in response to perinatal hypoxia and ischemia. Our results indicate a significant inverse relationship between the scores and the serum cortisol concentrations. Unlike the mode of delivery, the effects of perinatal hypoxia-ischemic insult on the HPA axis might persist for a prolonged period of more than 6 months of age (20).

Previous reports (21, 22) and our initial observation (11) indicated that the severity of illness and mechanical ventilation were probably not important factors in determining the pituitary-adrenal response. This study, however, demonstrated that VLBW infants requiring mechanical ventilatory support had significantly higher plasma ACTH and serum cortisol concentrations than those who were breathing spontaneously. The discrepancy was most likely caused by the larger sample size in the present series and thus greater statistical power, and the difficulty in selecting the representative parameters for grading the severity of illness (21, 22). A gradual decrease in serum cortisol concentrations despite an increase in plasma ACTH levels from day 7 to day 14 in nonventilated infants indicated a distinct pattern of postnatal adaptation of the pituitary and adrenal glands after birth (21) (Fig. 1). Such changes were not observed in infants requiring mechanical ventilation, because the serum cortisol concentrations continued to increase at day 14 (Fig. 2). This effect could be the result of severe stress associated with the underlying clinical condition or positive pressure ventilation that interfered with the usual pattern of hormone changes after delivery. Furthermore, we have observed that the plasma ACTH concentrations were similar in both ventilated and nonventilated infants at day 14 (Figs. 1 and 2). The exact mechanism responsible for this apparent dissociation between ACTH and cortisol response in ventilated infants at day 14 is not fully understood. A similar observation has been described in critically ill adult patients under prolonged stress and was suspected to be the result of HPA axis modulation by various vasoactive peptides (23). High endothelin levels may exert a positive drive on the adrenal glands, and secretion of atrial natriuretic hormone has an inhibitory effect on the hypothalamic-pituitary centers (23).

In summary, our findings suggest that a standard or multiple courses of antenatal dexamethasone for prevention of RDS have no long-lasting suppressive effects on the pituitary-adrenal function in preterm VLBW infants at day 7 or later. However, further studies with larger sample sizes are required to confirm the safety of multiple courses of antenatal corticosteroids. Maturation of the pituitary center appears to be more advanced compared with the adrenals. The organ’s ability to respond appropriately to various stressful stimuli and the lack of any significant association at day 14 between blood hormone concentrations and birth weight, gestational, or postconceptional age, indicate that the pituitary-adrenal axis is highly responsive at these early gestational ages (11).

Received May 7, 1997.

Accepted August 4, 1997.

	References

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