Original
Article
. . . . .
. . . . . . . . .
Effect of Dexamethasone Therapy on Serum Vitamin E
Concentrations in Premature Infants with Bronchopulmonary
Dysplasia
Sanjiv B. Amin, MD
Nirupama Laroia, MD
Robert A. Sinkin, MD
James W. Kendig, MD
OBJECTIVE:
difference in vitamin E intake between baseline and post-dexamethasone
therapy.
CONCLUSION:
Dexamethasone therapy in premature infants induces significant increase
in serum vitamin E concentrations to pharmacological levels independent
of vitamin E intake.
Journal of Perinatology (2003) 23, 552–555. doi:10.1038/sj.jp.7210984
To investigate the effect of dexamethasone therapy on serum vitamin E
concentrations in premature infants with bronchopulmonary dysplasia.
STUDY DESIGN:
A total of 10, 24 to 29 weeks’ gestational age, infants enrolled in a
prospective study designed to evaluate the effect of dexamethasone on
lipid intolerance were eligible for the study. Eight of these 10 infants had
serum vitamin E concentrations measured simultaneously with serum
triglyceride concentrations before the start of dexamethasone therapy
(baseline) and within 5 days of the initiation of dexamethasone therapy.
Charts were reviewed for vitamin E intake at baseline and on
dexamethasone therapy for each of these eight infants.
RESULTS:
All eight infants had physiological serum vitamin E concentrations (1 to
3 mg/dl) at baseline, while six of eight infants had pharmacological
serum vitamin E concentrations (Z3 mg/dl) on dexamethasone therapy.
All infants with an increase in serum vitamin E concentration also had a
simultaneous increase in serum triglyceride concentrations with a
significant correlation between vitamin E and triglyceride concentrations
(Spearman’s r ¼ 0.92). There was a significant difference in mean
serum vitamin E concentration between baseline and post-dexamethasone
therapy (P ¼ 0.01, Wilcoxon’s signed-rank test). There was no significant
Department of Pediatrics, Division of Neonatology, Children’s Hospital at Strong University of
Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Current address of Sanjiv B. Amin: Department of Pediatrics, University of Maryland School of
Medicine, USA.Current address of James W. Kendig: Department of Pediatrics, Penn State
Children’s Hospital, M.S. Hershey Medical Center, USA.
Address correspondence and reprint requests to Sanjiv B. Amin, MD, Division of Neonatology,
22 South Greene Street, Room N5W68, University Center, Baltimore, MD 21201-1595, USA
INTRODUCTION
Vitamin E, a major biological antioxidant, inhibits peroxidation of
membrane lipids by scavenging free radicals.1 Vitamin E has been
extensively investigated for the prevention and treatment of
retinopathy of prematurity (ROP) at physiological (1 to 3 mg/dl)
and pharmacological (3 to 5 mg/dl) serum concentrations with
conflicting results.2–8 A recently conducted meta-analysis of the
published randomized clinical trials of vitamin E prophylaxis to
reduce ROP demonstrated a decreased incidence for Stage 3+ROP
in the vitamin E treated group as compared to the control group.9
Based on the findings of this meta-analysis, it has been suggested
that the role of vitamin E in reducing severe ROP in premature
infants should be re-evaluated.
Currently, there are conflicting results on the effect of
dexamethasone on the incidence of ROP.10–13 Dexamethasone is
known to increase serum concentrations of vitamin A, but its effect
on concentrations of vitamin E, which is also a fat-soluble vitamin,
has not been previously described.14,15 We describe a clinical–
laboratory observation of the effect of dexamethasone on vitamin E
concentrations during a prospective clinical study conducted to
investigate lipid intolerance in neonates on dexamethasone therapy
for bronchopulmonary dysplasia.16
METHODS
The 10 premature infants enrolled in a prospective study designed
to evaluate the effect of dexamethasone on lipid intolerance were
eligible for the study.16 The subjects were enrolled between
November 1995 and July 1997. This study was approved by
Institutional Research Review Board of University of Rochester and
Journal of Perinatology 2003; 23:552–555
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Effect of Dexamethasone Therapy
Amin et al.
informed consent was obtained from the parents. The study was
prospective with patients serving as their own controls. The subjects
were between 24 and 29 weeks’ gestational age (GA) at birth and
had early BPD at the time of study. GA was assessed by obstetric
history, or if obstetric history was unreliable, by the Ballard
examination. The diagnosis of BPD was determined by the clinical
staff based on chest radiographs and increasing FiO2 requirements.
Dexamethasone was used at the discretion of the attending
neonatologist. Dexamethasone therapy followed the protocol of
Avery: 0.25 mg/kg every 12 hours for the first six doses, followed by
0.15 mg/kg every 12 hours for the next six doses, and a gradual
wean thereafter.17 To evaluate lipid metabolism, patients with a
known genetic disorder, active infection, prior lipid intolerance,
thyroid problems, surgery within 72 hours of the study, bleeding
manifestations and patients requiring an epinephrine or insulin
drip were excluded. During the study period, for 5 days after
initiation of dexamethasone therapy, lipid intake was kept constant
unless hypertriglyceridemia (triglyceride levels >250 mg/dl
(2.82 mmol/l)) developed.
Eight of these 10 infants had serum vitamin E (a tocopherol)
concentrations measured at baseline (before the start of
dexamethasone therapy) and within 5 days of the initiation of
dexamethasone therapy (post-dex). Serum vitamin E
concentrations are routinely measured in our unit to monitor
vitamin E status of premature infants. Serum vitamin E
concentrations were measured by high-performance liquid
chromatography (HPLC). Serum triglyceride concentrations,
measured simultaneously with vitamin E, before and after the
initiation of dexamethasone therapy, were also available for each of
the eight infants. Serum triglyceride concentrations were measured
using a standard colorimetric method (Ortho Clinical Diagnostics,
Raritan, NJ). Vitamin E/triglyceride ratios were calculated for each
of these eight subjects. Charts were reviewed for vitamin E intake at
baseline and during the study interval (post-dex). Charts were also
reviewed for clinical findings, suggesting vitamin E deficiency or
toxicity such as generalized edema, thrombocytosis, necrotizing
enterocolitis (NEC) and sepsis during the study period.
Statistical Analysis
Wilcoxon’s signed-rank test was used to analyze paired
measurements with the hypothesis that the mean difference
between the paired measurements is zero (Stata Program; Stata
Corporation, College Station, TX). Correlation analysis was
performed using Spearman’s correlation. All tests were two-sided
and a p-value of <0.05 was considered statistically significant.
RESULTS
The mean postmenstrual age of the eight infants at the initiation
of dexamethasone therapy was 284/7 weeks (range, 273/7 to 294/7
weeks) with a mean chronological age of 17 days (range, 10 to 28
days). All eight infants were appropriate for GA. Six out of the eight
infants were female. There were no significant differences in the
mean postmenstrual age and the mean chronological age between
six infants, in whom vitamin E concentrations rose following
dexamethasone therapy and two infants in whom it did not. Both
the infants in whom vitamin E concentration did not increase
following dexamethasone therapy were female.
There was no significant difference in the mean vitamin E
intake between baseline (2.8 U/kg/day) and post-dexamethasone
therapy (2.2 U/kg/day) among the eight infants (Table 1,
p ¼ 0.27). None of these eight infants were receiving any
supplemental vitamin E therapy prior to dexamethasone therapy.
Mean serum vitamin E concentrations, triglyceride concentrations
and vitamin E:triglyceride ratios at baseline and after the initiation
of dexamethasone therapy among the study subjects are shown in
Table 1. There was an increase in vitamin E concentrations in
seven of eight neonates after dexamethasone therapy with a mean
vitamin E concentration on dexamethasone (3.5 mg/dl)
significantly higher than the mean baseline vitamin E
concentration (2.1 mg/dl) (Figure 1, Table 1). All neonates had
physiological serum vitamin E concentrations (1 to 3 mg/dl) at
baseline, while six of eight infants had pharmacological serum
vitamin E concentrations (Z3 mg/dl) on dexamethasone
(Figure 1). All infants with an increase in serum vitamin E
concentrations also had a simultaneous increase in serum
triglyceride concentrations with a significant correlation between
vitamin E and triglyceride concentrations (p ¼ 0.005, Spearman’s
r ¼ 0.92) (Figure 2). Vitamin E:triglyceride ratios were similar
before and after the initiation of dexamethasone therapy. None of
the infants had clinical evidence of vitamin E deficiency or toxicity.
Table 1 Vitamin E Intake (U/kg/day), Serum Vitamin E Concentrations (mg/dl), Serum Triglyceride Concentrations (mg/dl) and Vitamin
E:Triglyceride Ratios at Baseline and After the Initiation of Dexamethasone Therapy Among the Study Subjects
Pre-dex therapy (n=8)
Vitamin E intake*
Serum vitamin E concentrations*
Serum triglyceride concentrations*
Vitamin E/triglyceride ratio*
2.8±0.77
2.12±0.41
119±34
0.018±0.003
Post-dex therapy (n=8)
2.2±1.1
3.56±1.2
298±118
0.012±0.003
p-Value
NS
0.01
0.007
NS
*Mean±SD.
Journal of Perinatology 2003; 23:552–555
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Amin et al.
Effect of Dexamethasone Therapy
6
Pre-dex
Serum vitamin E concentrations (mg/dl)
5
Post-dex
4
3
2
1
0
2
1
4
3
5
Subjects
6
7
8
Figure 1. Serum vitamin E concentrations at baseline (pre-dex) and
after (post-dex) the initiation of dexamethasone therapy for each
individual subjects.
500
Pre-dex
Serum triglyceride concentrations (mg/dl)
450
Post-dex
400
350
300
250
200
150
100
50
0
1
2
3
4
5
Subjects
6
7
8
Figure 2. Serum triglyceride concentrations at baseline (pre-dex) and
after (post-dex) the initiation of dexamethasone therapy for each
individual subjects.
DISCUSSION
Our study demonstrates that dexamethasone therapy causes an
acute increase in serum vitamin E concentrations, independent of
vitamin E intake. A similar effect on vitamin A, also a fat-soluble
vitamin, has been demonstrated previously.14,15 Both vitamins A
and E are stored in adipose tissue and liver. However, compared to
554
the circulating vitamin A, which is bound to retinol binding
protein and transthyretin, vitamin E is primarily circulated bound
with lipoproteins. The mechanism by which steroids increase
serum vitamin E concentrations has not been studied. We speculate
that the increase in serum vitamin E concentration observed with
dexamethasone usage may be secondary to the increase in serum
lipids, or independently by causing the release of vitamin E from
storage sites. It has been previously shown that with the increase in
serum lipids, vitamin E appears to be released from the cellular
membrane compartment into circulating lipoprotein, increasing
the absolute concentrations of plasma vitamin E.18 Because of this
relation with serum lipids, it has been suggested that the ratio of
vitamin E to total lipid or vitamin E to lipid fraction may be a
more useful way to measure vitamin E status.19,20 However, there is
little information available regarding optimum ratios for vitamin E
to total lipid or vitamin E to lipid fraction (triglyceride or
cholesterol) in premature infants.
Although six out of eight infants had an increase in vitamin E
concentrations to a pharmacological concentration on
dexamethasone therapy, ratios of vitamin E to triglyceride were not
increased on this therapy. Moreover, only infants with increases in
serum triglyceride concentrations on dexamethasone therapy had
increases in serum vitamin E concentrations. This indicates that
an increase in the serum vitamin E concentration is partly due to
an increase in serum lipid levels.
Hypertriglyceridemia following dexamethasone therapy has been
recently demonstrated in premature infants.16,21 In these studies,
occurrence of hypertriglyceridemia was dependent on the
dexamethasone dosage. A decrease in triglyceride concentration was
observed with a decrease in dexamethasone dosage.16 Because of
the marked dependence of plasma vitamin E values on lipid
concentration, we speculate the effect of dexamethsone on vitamin
E concentrations to be also dose dependent.
In neonates, prolonged exposure to pharmacological serum
concentrations of vitamin E has been associated with an increased
incidence of late-onset sepsis and NEC.8 None of the study subjects
had sepsis or NEC during the study period. Premature infants are
at an increased risk for the development of the clinical syndrome of
vitamin E deficiency, which is characterized by generalized edema,
hemolytic anemia, reticulocytosis and thrombocytosis.22 Since none
of these infants had clinical evidence of vitamin E deficiency
during the study period, we can presume the ratios observed do not
suggest vitamin E deficiency.
In summary, dexamethasone increases the absolute
concentration of vitamin E but not lipid adjusted vitamin E
concentrations. Future studies evaluating the role of steroids or
vitamin E in reducing ROP should take into consideration the
interaction between dexamethasone and serum vitamin E
concentrations. The usefulness of vitamin E to total lipid or
vitamin E to lipid fraction at pharmacological vitamin E levels also
needs to be investigated in premature infants while evaluating the
beneficial or toxic effects of vitamin E.
Journal of Perinatology 2003; 23:552–555
Effect of Dexamethasone Therapy
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