Published online October 31, 2008
PEDIATRICS Vol. 122 No. 5 November 2008, pp. 978-987 (doi:10.1542/peds.2007-3409)
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ARTICLE

Effects of Neonatal Dexamethasone Treatment on the Cardiovascular Stress Response of Children at School Age

Rosa Karemaker, MDa,b, John M. Karemaker, PhDc, Annemieke Kavelaars, PhDa, Marijke Tersteeg-Kamperman, PhDa, Wim Baerts, MDd, Sylvia Veen, MDe, Jannie F. Samsom, MDf,{dagger}, Frank van Bel, MDb and Cobi J. Heijnen, PhDa

a Laboratory of Psychoneuroimmunology
b Department of Neonatology, University Medical Center Utrecht, Utrecht, Netherlands
c Department of Physiology, Academic Medical Centre, Amsterdam, Netherlands
d Department of Neonatology, Isala Clinics Zwolle, Zwolle, Netherlands
e Department of Neonatology, University Medical Center Leiden, Leiden, Netherlands
f Department of Neonatology, Free University Medical Center, Amsterdam, Netherlands


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. The goal was to investigate cardiovascular responses to a psychosocial stressor in school-aged, formerly premature boys and girls who had been treated neonatally with dexamethasone or hydrocortisone because of chronic lung disease.

METHODS. We compared corticosteroid-treated, formerly preterm infants with formerly preterm infants who had not been treated neonatally with corticosteroids (reference group). Children performed the Trier Social Stress Test for Children, which includes a public speaking task and a mental arithmetic task. Blood pressure was recorded continuously before, during, and after the stress test. Plasma norepinephrine levels were determined before the test, directly after the stress task, and after recovery.

RESULTS. Overall, in response to stress, girls had significantly larger changes in systolic blood pressure and mean arterial pressure and in stroke volume and cardiac output, compared with boys. Boys exhibited larger total peripheral resistance responses, compared with girls. The hydrocortisone group did not differ significantly from the reference group in any of the outcome measures. However, dexamethasone-treated children had smaller stress-induced increases in systolic and mean arterial blood pressure than did hydrocortisone-treated children. In addition, the dexamethasone group showed smaller increases in stroke volume and blunted norepinephrine responses to stress, compared with children in the reference group. Correction for gender did not affect these results.

CONCLUSIONS. The differences in cardiovascular stress responses between girls and boys are consistent with known gender differences in adult cardiovascular stress responses. Our data demonstrate that neonatal treatment with dexamethasone has long-term consequences for the cardiovascular and noradrenergic stress responses; at school age, the cardiovascular stress response was blunted in dexamethasone-treated children. Hydrocortisone-treated children did not differ from the reference group, which suggests that hydrocortisone might be a safe alternative to dexamethasone for treating chronic lung disease of prematurity.

Key Words: cardiovascular • corticosteroids • follow-up studies • neonatology • retrospective clinical study

Abbreviations: CLD—chronic lung disease • TSST-C—Trier Social Stress Test for Children

In past decades, the use of neonatal corticosteroid therapy to treat or to prevent chronic lung disease (CLD) of prematurity was common practice. A few human follow-up studies have since been published, showing adverse long-term effects on behavior, neurologic and motor development, and hypothalamic-pituitary-adrenal responsiveness and the immune response.1–7 The corticosteroid most widely used for treatment of CLD is dexamethasone.2,8 However, since the first study was published in the 1970s by Baden et al,9 our hospital has instead used hydrocortisone.6 Although corticosteroid therapy for newborns is now actively discouraged, neonatologists continue to use it if other options fail.1,10,11 Consequently, there still are and will be large numbers of children affected by the possible long-term effects of neonatal corticosteroid treatment.

The full scope of the lifelong effects of neonatal corticosteroid treatment has mainly been evaluated in rats. The developmental stage of a newborn rat is comparable to that of the human fetus during the third trimester of pregnancy.12,13 Recent studies showed that rats treated with dexamethasone on days 1, 2, and 3 of life had a shorter life span and died as a result of cardiomyopathy and renal failure.14 Moreover, neonatal dexamethasone treatment of rats inhibits cardiomyocyte proliferation and is associated with increased cardiomyocyte volume at adult age.15,16 Functionally, dexamethasone-treated rats exhibit cardiac systolic dysfunction during their lifetime.17

Acute and transient cardiovascular adverse effects of neonatal dexamethasone treatment have been described for human patients, although conflicting data exist.17–19 However, little is known about possible long-term effects of neonatal dexamethasone treatment on the human cardiovascular system. It is well known from human research that an altered cardiovascular response to stress is an early predictor of an increased risk for cardiovascular disease in later life.20,21 Measurement of blood pressure and heart rate before, during, and after stress is a valuable method to investigate the cardiovascular stress response. Various noninvasive methods of blood pressure measurements have been applied, with the Finapres and Portapres systems (Finapres, Portapres, and Modelflow are registered trademarks, presently marketed by Finapres Medical Systems, Amsterdam, Netherlands), based on the volume-clamp method described by Penáz22 and developed by the Dutch TNO Biomedical Instruments Group,23 being common, well-validated, equipment choices.24,25

The Trier Social Stress Test for Children (TSST-C)26 is a widely used inducer of psychosocial stress, consisting mainly of public speaking and mental arithmetic in front of an audience. We reported recently on the activity of the immune system and the hormonal (corticotrophin and cortisol) responses to the TSST-C in the same cohort.27

Previous animal studies showed pulmonary and systemic hypertension in adult rats treated neonatally with dexamethasone.14,27,28 Therefore, we hypothesized that neonatal exposure of prematurely born children to corticosteroids might be associated with increased blood pressure at rest and an altered cardiovascular response to the TSST-C, as determined at school age. To investigate the long-term effects of neonatal corticosteroid treatment on cardiovascular responses to a psychosocial stressor, we studied school-aged, formerly premature boys and girls who had been treated with dexamethasone or hydrocortisone because of CLD.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
In a retrospective, matched-cohort study, we compared the long-term effects of neonatal treatment with 2 different corticosteroids (dexamethasone and hydrocortisone) and included a reference group consisting of formerly premature infants who had not been treated with steroids neonatally. As reported previously,27 the study population consisted of prematurely born infants who were admitted between December 1993 and July 1997 to the NICUs of the University Medical Centre Utrecht, the Leiden University Medical Centre, the Free University Medical Centre Amsterdam, and the Isala Clinics Zwolle in the Netherlands. The study was approved by the medical ethics committee of the University Medical Centre Utrecht and the scientific boards of the participating hospitals. Written parental consent was always obtained. The NICU of the University Medical Centre Utrecht used exclusively hydrocortisone therapy to reduce CLD, in a treatment regimen starting with 5 mg/kg per day and tapering to 1 mg/kg per day over a 22-day period, whereas the other hospitals used dexamethasone for this purpose, starting with 0.5 mg/kg per day and tapering to 0.1 mg/kg per day over a 21-day period. In all centers, glucocorticoid treatment was sometimes extended or shortened, depending on the responses to and acute adverse effects of therapy. In all instances, treatment was used as a rescue modality, that is, when it was impossible to wean the infant from the ventilator, with prolonged dependence on supplementary continuous oxygen (fraction of inspired oxygen of >0.30), in the initial phase of CLD. The average age at the start of glucocorticoid treatment is presented in Table 1.


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  		TABLE 1 Perinatal and Neonatal Characteristics

 
The decision to treat was always left at the discretion of the attending neonatologist. In addition to the 2 groups treated with glucocorticoids neonatally, a group of prematurely born infants not treated with glucocorticoids in the neonatal period was included for comparison.

Study Groups
Eligibility for inclusion in one of the study groups were (1) surviving the neonatal period; (2) availability to participate in the study protocol, as indicated below; (3) neonatal cerebral ultrasound scans showing maximally grade II periventricular hemorrhage, classified as described by Papile et al29; and (4) absence of major congenital anomalies. Infants with periventricular leukomalacia also were excluded. The hydrocortisone and dexamethasone groups were constituted as follows. The charts of all consecutively admitted, preterm infants born at <32 weeks of pregnancy in the participating hospitals were reviewed systematically. The NICU of the University Medical Centre Utrecht used only hydrocortisone, and 131 eligible infants were treated with hydrocortisone during the defined time period. The dexamethasone group, which was recruited in a similar way from the 3 hospitals that used only dexamethasone for reduction of CLD, consisted of 198 eligible infants. Children from the dexamethasone and hydrocortisone groups were matched with respect to gestational age, birth weight, gender, year of birth, severity of infant respiratory distress syndrome (determined according to clinical symptoms and the classification system described by Giedeon et al,30 that is, no, moderate, or severe respiratory distress syndrome), and whether minor periventricular/intraventricular hemorrhage (grade I or II) was present. During the initial phase of recruitment, a total of 37 children eligible for the reference group, 29 children for the hydrocortisone group, and 28 children for the dexamethasone group declined to participate. Ultimately, 52 individuals from the hydrocortisone group could be matched with 52 from the dexamethasone group.

Fifty-two participants in the reference group were also recruited from the 4 participating hospitals (50% from the University Medical Centre Utrecht and the others equally distributed over the other hospitals). The reference group consisted of prematurely born infants who had not been treated with glucocorticoids neonatally and did not have periventricular leukomalacia, major periventricular/intraventricular hemorrhage (grade III or more), or any other major complications during the neonatal period. Although we tried to match this latter group, with respect to gender, birth weight, and gestational age, with a dexamethasone/hydrocortisone couple, this was not always possible (Table 1).

If a child did not understand the TSST-C and subsequently did not show any signs of stress, defined as an increase in either heart rate and/or blood pressure, the results were excluded from the analysis (n = 3). Two girls refused to participate. Technical problems for 17 children resulted in 139 children having their blood pressure recorded with a Portapres system throughout the experiment.

Preparation and Timing of the TSST-C
Parents were asked to ensure that their children did not consume foods or medication that might interfere with blood pressure regulation or norepinephrine reactivity. Twenty-four hours before the visit to the hospital, a dietary list was provided for this purpose. On the test day, children first underwent a physical examination, including manual blood pressure measurements on both arms when seated (Table 2). Parents were asked to limit the amount of fluids their children consumed at lunchtime to a maximum of 250 mL. Preparation for the stress test started at 1:15 PM, at which time an antecubital intravenous line for blood sampling was inserted (ie, 45 minutes before rest period 1 started). The actual TSST-C public speaking task was performed between 2:45PM and 3:15 PM, under the direction of a researcher and a research nurse working together with a strict time schedule. All children were tested by these same 2 investigators.


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  		TABLE 2 Patient and Parent Characteristics at Follow-up Age

 
Portapres Application
In accordance with the original TNO Portapres protocol,23 the finger cuff was applied to the middle phalanx of the third finger in a standard manner. To correct the blood pressure level for gravitational effects of hand movements, the Portapres height correction device was taped to the child's chest at heart level.31 The child was seated dressed in a comfortable chair or wheelchair, with pillows to secure a stable upright sitting position throughout the experiment. The child's biometric data (ie, length, weight, and age) were entered into the control unit of the Portapres device and a test recording was made, with observation of the real-time blood pressure signal on a laptop computer, to ensure stable recording. After the initial physiologic calibration32 made by Portapres, the blood pressure signal became constant and reliable. Portapres was switched off and the cuff was left in place around the child's finger. Throughout the experiment, if the child indicated that he or she felt chilly, then blankets and a hand-warming muff were provided, to increase comfort and the reliability of Portapres recordings.24,33 The physiologic calibration feature (the internal self-control mechanism of Portapres, in which part of the pressure-volume measurement of the vascular bed of the finger is repeated to correct for a possible slow drift in blood pressure measurements, which results in loss of information for 2 or 3 heart beats per 70–90 beats) of Portapres was not switched off during the experiment.32

TSST-C Procedure
This test was described in full by Buske-Kirschbaum et al.26 In brief, the test consists of a 30-minute relaxation period in front of a video with neutral contents, a 10-minute preparation period, a 5-minute public speaking task, and a 5-minute mental arithmetic task (number subtraction). During the speaking task, children are given the beginning of a story by the investigator and are prompted to complete the story as excitingly as possible in front of a "committee" judging the child's performance. The difficulty level of the subsequent arithmetic task was adjusted to the mental development level of the tested child. After this 10-minute stress period, there was a 10-minute debriefing period, during which the children were praised for their excellent performance, followed by another 45-minute video with neutral contents. The 2 videos shown were the same for all participants. During the second video, Portapres was switched on for the last 20 minutes. After this last recording, the finger cuff and height corrector were removed, and the child was reunited with his or her parents.

Measurement of Norepinephrine Levels in Plasma
EDTA-treated blood for determination of plasma norepinephrine levels was collected on ice after rest period 1, immediately after the mental arithmetic task ended, and after rest period 2 (Fig 1). Plasma was frozen rapidly at –80°C, and norepinephrine levels were determined with an enzyme-linked immunosorbent assay (DLD Diagnostika, Hamburg, Germany).


Figure 1
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  		FIGURE 1 Schedule for the TSST-C, providing an overview of sampling periods for the different blood pressure measurements and norepinephrine (NE) sampling.

 
Data Analysis
Portapres data were analyzed by using Modelflow software (FMS, Amsterdam, Netherlands),34 which rendered measurements of systolic, diastolic, and mean arterial pressure and heart rate, with subsequent pulse contour analysis-based estimates of stroke volume, cardiac output, and total peripheral resistance.23 For every child, 10 periods of 30-second duration25,35 were selected, whereby physiologic calibrations were excluded.32 The 10 selected periods were representative of the different phases of the TSST-C, that is, (1) rest period 1 with video, (2) beginning of instruction on the TSST-C, (3) end of story preparation phase, (4) start of telling the story, (5) end of telling the story, (6) start of arithmetic task, (7) end of arithmetic task, (8) start of debriefing phase, (9) end of debriefing phase, and (10) rest period 2 (Fig 1).

Because it is known that there is large interindividual variability in blood pressure results measured with the Portapres system,25 the blood pressure values and Modelflow output data for each child were transformed into data relative to the first rest period for each child by setting the value measured in rest period 1 at 1.0. The outcome measures for the other 9 periods were recalculated as fractions relative to rest period 1. In this way, each child served as his or her own control, and data were comparable between subjects. Only these relative data were used to compare the outcomes of treatment groups. Because the experiments were conducted over a period of 2 years, we compared early and later measurements to validate internally our measurements and their stability. We found no difference between the early and later measurements (data not shown), and we concluded that our measurements were comparable over the time it took to complete the inclusions for this study.

Portapres and norepinephrine data were analyzed by using SPPS 13.0.1 (SPSS, Chicago, IL), with repeated-measurement analysis. Because all data were normalized to the value at rest period 1 and all children returned approximately to this value in rest period 2 (data not shown), the relaxation periods before and after the TSST-C were not included in the final analysis, and the repeated measurements were analyzed over the 8 periods that represented the actual TSST-C.

Outliers were excluded before SPSS analysis, and posthoc analysis was performed by using Bonferroni's correction, to compensate for multiple comparisons. Gender differences were analyzed by using the same methods, and a group-gender interaction was investigated for all cardiovascular indices. This resulted, in effect, in a 3 x 2 study design. All P values for treatment group differences mentioned in the text were corrected for gender, unless otherwise specified. A P value of <.05 was considered statistically significant. Because it was known that factors such as BMI, social status, birth weight, and age at the time of testing were possible confounders of blood pressure, we tested whether there were any significant covariates present to be included in our analysis (see Tables 1 and 2 for all covariates investigated). No significant covariates were identified in our database, however, and these variables were not included in data analyses.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
As described above, 139 of the 156 children included in this study performed the TSST-C and had their blood pressure recorded. Basic characteristics at birth and at follow-up assessment are provided in Tables 1 and 2. In data analysis, it seemed that, for 29 children, the recording was not stable during the entire time of the TSST-C, defined as a recorded period of >30 seconds between physiologic calibrations.24 We could reliably analyze data for 33 children in the reference group, 41 in the hydrocortisone group, and 36 in the dexamethasone group. The characteristics of these 110 children did not differ from those of the total group of 139 children who performed the TSST-C (Tables 1 and 2).

To exclude a genetic component in blood pressure responses, we asked the parents of participating children about the prevalence of cardiovascular disease, hypercholesterolemia, and diabetes mellitus in their first-degree relatives. There were no differences between treatment groups (data not shown). In the morning before the stress test, there were no group differences in baseline blood pressure (measured with classic manometry) or seated heart rate (Table 2).

Blood Pressure Response to the Stressor
In response to the TSST-C, systolic, diastolic, and mean arterial pressure increased and reached maximal values at time point 4, during the speech task. At time point 9, after the 10-minute debriefing period, all blood pressure values had returned to the initial levels of the preparation period (Fig 2, restricted to mean pressures for clarity). In view of the strong parallel between mean and diastolic pressure outcome values, we limit the description to systolic and mean pressure values only.


Figure 2
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  		FIGURE 2 Relative mean arterial pressure (MAP) during the TSST-C. Error bars represent SEM. Time points on the x-axis correspond to the time points shown in Fig 1. REF indicates reference; HC, hydrocortisone; DEX, dexamethasone (dexamethasone, n = 36; hydrocortisone, n = 41; reference, n = 33; dexamethasone versus hydrocortisone, P = .04; dexamethasone versus reference, not significant; hydrocortisone versus reference, not significant).

 
When we analyzed group differences in mean arterial and systolic blood pressure responses to the stressor, we observed a lower response in dexamethasone-treated versus hydrocortisone-treated children (mean arterial, P = .04; systolic, P = .04), whereas the response of the hydrocortisone group was similar to that of the reference group (P = 1.0), after correction for gender. The difference between the dexamethasone group and the reference group did not reach statistical significance (Fig 2).

Girls overall showed a higher systolic stress response than did boys (P = .026). Although the treatment group-gender interaction did not reach statistical significance (P = .089), we cannot exclude the possibility that perinatal treatment contributed to this finding.

Cardiac Response to the Stressor
Similar to the observed blood pressure responses, the maximal increase in heart rate during the TSST-C was observed at time point 4. Immediately after termination of the stress task at time point 8, heart rate returned to initial levels in all groups (Fig 3).


Figure 3
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  		FIGURE 3 Relative heart rate response during the TSST-C. Error bars represent SEM. Time points on the x-axis correspond to the time points shown in Fig 1. REF indicates reference; HC, hydrocortisone; DEX, dexamethasone (dexamethasone, n = 36; hydrocortisone, n = 41; reference, n = 33; no significant group effects).

 
As depicted in Fig 3, the heart rate response to the TSST-C did not differ significantly between groups (P = .39). In addition, girls did not differ from boys in heart rate response (P = .133; data not shown).

The stress-induced change in stroke volume was smaller in the dexamethasone group than in the reference group (P = .012) (Fig 4) and tended to be lower in the dexamethasone group than in the hydrocortisone group (P = .075) after correction for gender. Girls had larger stroke volume changes than boys (P < .001), and there was no group-gender interaction for this parameter (P = .127). However, combined with slightly higher heart rate responses, these larger changes in stroke volume resulted in greater stress-induced alterations in cardiac output for girls than for boys (P < .001) (Fig 5). In addition, there was a significant group-gender interaction (P = .012). Nevertheless, we observed an overall difference in cardiac output (P = .001, after correction for gender), with dexamethasone-treated children having significantly lower cardiac output responsiveness than children in the other 2 groups (dexamethasone versus reference, P = .002; dexamethasone versus hydrocortisone, P = .001; hydrocortisone versus reference, P = 1.0, after correction for gender). Boys showed a significantly larger total peripheral resistance increase than did girls (P < .001) (Fig 6), but there was no effect of glucocorticoid treatment on the stress-induced change in total peripheral resistance (P = .699) and no group-gender interaction (P = .646) for this parameter (Fig 6).


Figure 4
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  		FIGURE 4 Relative stroke volume (SV) changes during the TSST-C. Error bars represent SEM. Time points on the x-axis correspond to the time points shown in Fig 1. REF indicates reference; HC, hydrocortisone; DEX, dexamethasone (dexamethasone, n = 36; hydrocortisone, n = 41; reference, n = 33; dexamethasone versus reference, P = .012; dexamethasone versus hydrocortisone, P = .075; reference versus hydrocortisone, not significant after correction for gender).

 

Figure 5
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  		FIGURE 5 Relative changes in cardiac output (CO) during the TSST-C, treatment group differences, and gender differences (A, girls, n = 62; B, boys, n = 77). Error bars represent SEM. Time points on the x-axis correspond to the time points shown in Fig 1. REF indicates reference; HC, hydrocortisone; DEX, dexamethasone (gender, P < .001; group, P = .001; group-gender interaction, P = .012; dexamethasone versus reference, P = .002; dexamethasone versus hydrocortisone, P = .001; hydrocortisone versus reference, P = 1.0, after correction for gender).

 

Figure 6
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  		FIGURE 6 Relative changes in total peripheral resistance (TPR) during the TSST-C, treatment group differences, and gender differences (A, girls, n = 62; B, boys, n = 77). Error bars represent SEM. Time points on the x-axis correspond to the time points shown in Fig 1. REF indicates reference; HC, hydrocortisone; DEX, dexamethasone (gender, P < .001; group, P = .699; group-gender interaction, P = .646).

 
Norepinephrine Response to the Stressor
Repeated-measures analysis of norepinephrine data revealed a significant effect of time (P < .0001) and a significant group effect (P = .040). The norepinephrine responses of children in the dexamethasone group were significantly lower than those of children in the reference group (P = .041), after correction for gender. The difference between the hydrocortisone and dexamethasone groups did not reach statistical significance (P = .166). The hydrocortisone group did not differ from the reference group (Fig 7). There was no gender difference in norepinephrine response (P = .372) or group-gender interaction (P = .22).


Figure 7
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  		FIGURE 7 Plasma levels of norepinephrine before, immediately after, and 60 minutes after the TSST-C. Error bars represent SEM. Time points on the x-axis correspond to the time points shown in Fig 1. REF indicates reference; HC, hydrocortisone; DEX, dexamethasone. *Significant difference between dexamethasone and reference groups, P < .05 (dexamethasone, n = 36; hydrocortisone, n = 41; reference, n = 33; dexamethasone versus hydrocortisone, P = .166; dexamethasone versus reference, P = .041; reference versus hydrocortisone, not significant after correction for gender.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We show here that neonatal dexamethasone treatment for CLD of prematurity has long-lasting consequences for the cardiovascular and norepinephrine responses to psychosocial stress at school age. The psychosocial stress-induced changes in systolic blood pressure, mean arterial pressure, and cardiac output in dexamethasone-treated children were significantly smaller than those in hydrocortisone-treated children. Moreover, the stress-induced changes in cardiac output and stroke volume were lower in the dexamethasone-treated group than in the reference group. Hydrocortisone-treated children did not differ from the reference group in their cardiovascular responses to psychosocial stress, in any of the parameters tested.

There are only a few publications on human cardiovascular follow-up evaluations after neonatal dexamethasone treatment. In 8 children treated neonatally with dexamethasone, no abnormalities were seen with echocardiography at 8 years of age, and no signs of hypertension were present.36 In another study, no differences in resting blood pressure for 68 dexamethasone-treated children versus 74 nontreated children at 13 to 17 years of age were observed.37 In both groups, however, the blood pressure was >95th percentile for height and age, which was attributed to premature birth, irrespective of neonatal steroid treatment.37 We also did not observe group differences in blood pressure at rest, but blood pressures were all within the reference range for height and age in our group of prematurely born children (Table 2). Although baseline heart rate and blood pressure were normal, the stress-induced changes in blood pressure were affected by neonatal dexamethasone treatment, which suggests that the capacity of the cardiovascular system to adapt to changes in the environment is blunted in dexamethasone-treated children.

In previous animal studies from this department, long-lasting morphologic changes of the heart in dexamethasone-treated animals, such as hypertrophy of cardiomyocytes and thickening of the left ventricular wall, were detected.38 Furthermore, neonatal dexamethasone treatment resulted in decreased systolic function and reduced heart weight at 4 weeks of age.39 This decrease in systolic function mimics the reduced systolic and mean arterial pressure responses we observed in dexamethasone-treated children. However, echocardiography performed at rest did not show a reduction in estimated heart weight or a difference in wall thickness between dexamethasone-treated, hydrocortisone-treated, and reference children.15 Given the many similarities we observed with neonatal dexamethasone treatment of rats and humans, we cannot exclude the possibility that morphologic changes may develop later in life among these children.

Investigation of gender-specific differences in the response to stress showed that girls reacted to the stressor with larger changes in systolic blood pressure, stroke volume, and cardiac output, compared with boys. The latter parameter was the only one that showed a group-gender interaction, but the treatment effect was maintained after correction for gender. Overall, boys showed higher total peripheral resistance responses, independent of perinatal treatment.

It is known that adult men and women differ in stress responses; women are considered to be predominantly cardiac responders, and men are considered to respond mainly through adaptation of their vascular resistance.40 Not much is known about gender differences at prepubertal ages, although hormones (mainly the difference in estrogen levels) are thought to be the main explanation for the differences seen in adults, because the gender differences in stress responses disappear after female menopause. The gender differences in stress responses observed in our study seemed to follow the adult stress response pattern,41 although the oldest child tested was no more than 10 years of age. However, the gender-specific responses to stress do not explain the significant differences between dexamethasone-treated children on the one hand and hydrocortisone-treated and reference children on the other; dexamethasone-treated children showed an overall blunted cardiovascular stress response. Therefore, our data do not allow us to pinpoint which gender is more at risk for developing cardiovascular dysfunction as a result of neonatal dexamethasone treatment.

Physiologically, the normal short-term response to a psychological stressor starts in the hypothalamic paraventricular nucleus, resulting in activation of the sympathetic nervous system. Epinephrine and norepinephrine are released from the adrenal medulla and postganglionic sympathetic nerve endings, respectively. Consequently, heart rate and cardiac contractility increase, with a decreased ejection time. In addition, given sufficient venous return, the inotropic β1-adrenergic effect of epinephrine plus norepinephrine increases stroke volume and, in conjunction with the increased heart rate, increases cardiac output. The {alpha}1-adrenergic effect of catecholamines causes peripheral vasoconstriction, increasing blood pressure and total peripheral resistance,42 opposing the nitric oxide-dependent muscle vasodilation.43,44 The increase in mean arterial blood pressure in response to the stressor was significantly lower in dexamethasone-treated children, compared with hydrocortisone-treated children. In addition, the combined increase in stroke volume and heart rate, and thus cardiac output, in reaction to the psychosocial stressor in the dexamethasone group was lower than that in the hydrocortisone group. The hydrocortisone group did not differ from the reference group. The most obvious explanation for our observations is that a lower sympathetic stress response results in lower plasma norepinephrine levels and consequently a blunted cardiovascular stress response. However, previous research showed that interindividual variability in vascular adrenergic responsiveness contributes to the balance of factors that maintain normal blood pressure in individuals with differing levels of sympathetic neural activity.45 Whether a clear group difference in sympathetic drive or altered adrenergic sensitivity and/or nitric oxide-driven muscle vasodilation is responsible for the reduced cardiovascular response to stress in the dexamethasone-treated children remains to be elucidated.

An alternative explanation for the blunted cardiovascular stress response observed in dexamethasone-treated children would be that these children perceived the stressor in a different way. However, as we reported earlier, we also analyzed the response of the hypothalamic-pituitary-adrenal axis (corticotropin and cortisol) as part of the same study. Although the overall activity of this axis was lower in the dexamethasone group, we did not observe group differences in stress-induced increases in corticotropin and cortisol levels.27 Therefore, we do not expect that differences in appraisal of the stressor underlie the observed blunted cardiovascular response to the stressor.

It remains an intriguing phenomenon that neonatal treatment with hydrocortisone does not show the long-term adverse effects that we observed with dexamethasone treatment. Hydrocortisone and dexamethasone differ in the dose used and in several genomic and nongenomic effects and vary in the binding specificity for mineralocorticoid and glucocorticoid receptors. van der Heide-Jalving et al6 established that hydrocortisone is as clinically effective as dexamethasone in mitigating short-term negative outcomes, such as ventilator dependence or the occurrence of CLD. This study provides original long-term data obtained in a carefully planned study. A weakness may be that it was not a randomized, controlled trial. Because there has been no randomized, long-term, follow-up trial of dexamethasone versus hydrocortisone, we strongly encourage, on the basis of the collective data now available, additional study of hydrocortisone as a safer alternative to dexamethasone for the treatment of CLD of prematurity.6,46 The similarities between the long-term consequences of neonatal dexamethasone treatment for rats and humans are a reason for serious concern, especially because we now know that, at adult age, dexamethasone-treated rats also display dysregulation of the immune system and the neuroendocrine system, severe nephropathy, and a significantly reduced life span.14,47–49

It will be of great importance to reexamine this cohort of formerly preterm infants, to investigate whether the observed differences are sustained and/or develop into risk factors for cardiovascular disease during the postpubertal period. Moreover, reinvestigation of this cohort might allow an early intervention to minimize or to prevent possible cardiovascular risks of early neonatal dexamethasone treatment.


   ACKNOWLEDGMENTS
 
This study was supported by a grant from the Catharijne Foundation and the Dirkzwager-Assink Fund.

We thank Jitske Zijlstra and Miriam Maas for performing all of the laboratory analyses.


   FOOTNOTES
 
Accepted Feb 22, 2008.

Address correspondence to Cobi J. Heijnen, PhD, Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Office KC03.068.0, Lundlaan 6, 3584 EA Utrecht, Netherlands. E-mail: c.heijnen{at}umcutrecht.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

There is growing concern with respect to possible adverse long-term effects of neonatal dexamethasone treatment of chronic lung disease of prematurity. Data from animal studies have shown that neonatal dexamethasone treatment can have long-lasting adverse effects on the cardiovascular system.

 

What This Study Adds

We report for the first time that human neonatal dexamethasone treatment has consequences for the cardiovascular response to a stressful challenge at school age. In contrast, we did not observe any effect of neonatal hydrocortisone treatment.

 

{dagger} Deceased. Back


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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