Published online October 2, 2006
PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1592-1599 (doi:10.1542/peds.2006-0973)
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ARTICLE

Follow-up of a Randomized, Placebo-Controlled Trial of Postnatal Dexamethasone: Blood Pressure and Anthropometric Measurements at School Age

Lisa K. Washburn, MDa, Patricia A. Nixon, PhDa,b and T. Michael O'Shea, MD, MPHa

a Department of Pediatrics, School of Medicine
b Department of Health and Exercise Science, Wake Forest University, Winston-Salem, North Carolina


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. The purpose of this work was to evaluate the effects of a 42-day tapering course of dexamethasone on blood pressure and anthropometric measurements in school-age children who were born with very low birth weight.

METHODS. Sixty-eight children, who as neonates participated in a randomized placebo-controlled trial of a 42-day tapering course of dexamethasone (n = 38, dexamethasone; n = 30, placebo) to facilitate weaning from the ventilator, were seen at a median of 9 years of age. Participants underwent measurements of systolic blood pressure, diastolic blood pressure, mid-arm circumference, triceps skinfold thickness, height, and weight. Mann-Whitney U tests were used to compare groups, and Spearman coefficients were used to examine correlations between variables.

RESULTS. Comparing dexamethasone- and placebo-treated children, we found no differences in systolic blood pressure, mid-arm circumference, triceps skinfold thickness, height, weight, or body mass index. Twenty-nine percent of all subjects had systolic blood pressure and/or diastolic blood pressure ≥90th percentile for age and gender. Thirty percent of all subjects had body mass index ≥85th percentile for age and gender.

CONCLUSIONS. In a group of preterm very low birth-weight infants at high risk for chronic lung disease, we found no effects of dexamethasone on blood pressure or anthropometric measurements at 8 to 11 years of age. Of concern is that a high proportion in this sample had blood pressure ≥90th percentile and/or body mass index ≥85th percentile.

Key Words: prematurity • children • glucocorticoid • very low birth weight • growth

Abbreviations: VLBW—very low birth weight • CLD—chronic lung disease • GCRC—General Clinic Research Center • BMI—body mass index • SBP—systolic blood pressure • DBP—diastolic blood pressure

Improvements in neonatal care have resulted in an increased rate of survival of very low birth-weight (VLBW) infants; however, the frequency of neonatal chronic lung disease (CLD) also has increased.1 Neonatal CLD has been associated with increased rehospitalizations in the first year of life,2,3 abnormal pulmonary function,4 poor growth, and neurodevelopmental impairments.5–7 Thus, there is much interest in treatments to prevent CLD.

In 1988, Cummings et al8 reported that preterm infants treated with a 42-day tapering course of dexamethasone had better pulmonary and neurodevelopmental outcomes than controls, and this treatment was used widely during the 1990s. After a meta-analysis of randomized trials suggested that treatment with dexamethasone was associated with an increase in neurologic impairment,9 the American Academy of Pediatrics and the Canadian Paediatric Society recommended that systemic corticosteroids be used only in randomized trials or in "exceptional clinical circumstances when the risk of mortality is high."10 However, a more recent meta-analysis suggests that systemic steroids might be an appropriate treatment for infants at high risk for CLD.11

The acute adverse effects of neonatal dexamethasone treatment include slowed growth12 and elevated blood pressure.13 Most studies suggest that the effects of dexamethasone on growth are transient,14–19 although in 1 study of early postnatal dexamethasone (given in the first 12 hours of life), dexamethasone was associated with lower height and weight at 2 years of age among boys20 and lower height at school age in boys and girls.21 Although less frequently studied, persistent effects on blood pressure have not been found.19,21 However, the power of previous studies to detect effects of dexamethasone has been limited by small sample size17,18 or contamination (ie, treatment with dexamethasone of infants randomly assigned to placebo).19,21

Here we report a comparison of blood pressure and growth among 8- to 11-year-old children who, as neonates, were randomly assigned to a 42-day tapering course of either dexamethasone or placebo to reduce the duration of ventilator dependence. Experiments in animals suggest that exposure to glucocorticoids during fetal life results in elevated blood pressure in adulthood,22,23 and antenatal exposure of human fetuses to glucocorticoids has been associated with elevated blood pressure in adolescence.24 Thus, we hypothesized that infants exposed to dexamethasone would have higher blood pressure at school age. Because both exposure to dexamethasone and the development of CLD (which was decreased by dexamethasone treatment) have been associated with slowed growth, we hypothesized that there would be no effects of dexamethasone on growth at school age.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was approved by the Institutional Review Board and the General Clinic Research Center (GCRC) of the Wake Forest University Baptist Medical Center and Forsyth Medical Center. Parents gave written informed consent, and children gave assent.

Subjects
All of the subjects in this study had participated previously in a randomized, placebo-controlled trial of dexamethasone to reduce the duration of ventilator dependence of VLBW neonates.25 Of those 118 children, 95 survived to 1 year adjusted age, and 68 (72%) of these surviving children participated in the current study. Twelve subjects could not be located, 1 subject declined participation, and 5 parents declined participation. Nine subjects expressed interest in participating but were unable to be evaluated despite multiple scheduled appointments; for 2 of these subjects, consent was given to obtain height, weight, and blood pressure data from their primary care physician. The sample of 68 children provided 80% power to detect group differences of ~8 mmHg in blood pressure, ~7 cm in height, and ~9 kg in weight.

Children were examined at 8 to 11 years of age. All were born between April 1992 and May 1995 and met eligibility criteria for the randomized trial alluded to above, which were: (1) birth weight <1501 g, (2) age 15 to 25 days, (3) lack of weaning of ventilator settings, (4) absence of clinical signs of sepsis, and (5) absence of patent ductus arteriosus by echocardiography.25 The treatment group received dexamethasone at an initial dose of 0.5 mg/kg per day that was tapered over 42 days.8,25 The participants were not treated with open-label dexamethasone.

Data on neonatal characteristics and the diagnosis of CLD were obtained by a research nurse from medical charts. CLD was defined as the use of supplemental oxygen at 36 weeks' postmenstrual age.26 The assignment of gestational age in completed weeks was based on the date of the mother's last menstrual period unless this was not available, in which case an obstetrician's estimate was used. When no prenatal estimate was available, gestational age was based on assessment of the neonate. Infants whose mothers were treated with betamethasone or dexamethasone (any number of doses) before delivery were considered to have had antenatal steroid exposure. Birth weight z value, a continuous measure of birth weight for gestational age, was determined from published tables derived from recent US natality data.27

Procedures and Measurements
Blood pressure was measured with an automated oscillometric device (Alaris medical systems, Model 4410; Cardinal Health, Dublin, OH) by GCRC nursing staff certified in blood pressure measurement. The guidelines established by the National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents were used to determine proper cuff size.28 The participant was seated quietly for 5 minutes with the forearm at heart level and feet on the floor. Three measurements of blood pressure were made with 1 minute of rest in between.29 The average of the measurements was used to estimate systolic and diastolic blood pressure. Age- and gender-specific oscillometric blood pressure standards for children were used to determine blood pressure percentile groups.30 Participants found to have high normal (≥90th percentile) or high blood pressure (≥95th percentile) were referred (if consent given) to their primary care provider for further management, because the diagnosis of hypertension requires elevated blood pressures on 3 separate occasions.31

Anthropometric measurements were made in triplicate by nutritionists in the GCRC. Mid-arm circumference was measured to the nearest centimeter with a measuring tape. Triceps skinfold thickness was measured to the nearest millimeter with a Lange skinfold caliper. Height without shoes was measured to the nearest tenth of a centimeter using a wall-mounted stadiometer. Weight in light clothing without shoes was measured to the nearest tenth of a kilogram using a digital platform scale. Body mass index (BMI) and percentiles and z values for height, weight, and BMI were derived using Epi-info 2000 (Centers for Disease Control and Prevention, Atlanta, GA).32 Z values for mid-arm circumference and triceps skinfold thickness were determined using reference data from the National Health and Nutrition Examination Survey (1999–2002).33 Children with BMI ≥95th percentile for age and gender were classified as overweight, and children with BMI ≥85th percentile but <95th percentile were classified as at risk for overweight.34

The individuals performing all of the measurements were not aware of the child's postnatal exposure (dexamethasone or placebo). Parents were informed of their child's random assignment group at follow-up if requested.

Data Analysis
SPSS software (version 14.0, SPSS Inc, Chicago, IL) was used to analyze the data. Descriptive analyses were performed to examine measures of central tendency and dispersion. For univariate analyses, {chi}2 tests and the Mann-Whitney U test were used when comparing groups with respect to categorical and continuous variables, respectively. Spearman correlational analysis was used to examine the relationships between blood pressure and anthropometric measurements. Linear regressions models were used to estimate dexamethasone effects, adjusted for potential confounders. To investigate whether the effect of dexamethasone was influenced by the postmenstrual age at which treatment was initiated, we used linear regression to estimate the regression coefficient for the interaction of treatment and postmenstrual age at initiation of treatment. A P < .05 was considered to be statistically significant.


   RESULTS
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DISCUSSION
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In Fig 1, the follow-up status is shown for the 118 participants in the randomized, controlled trial of dexamethasone. As shown in Table 1, prerandomization attributes of children who participated in the randomized trial were similar for those seen and not seen in the current study. Among participants in the current study, a greater proportion of children in the dexamethasone-treated group were exposed to antenatal steroids. Inclusion of data obtained from primary care providers for 2 children did not alter the results of the study; therefore, these data are not included in the results described here.


Figure 1
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  		FIFURE 1 Flow diagram for study participants in the randomized, controlled trial of postnatal dexamethasone.

 

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  		TABLE 1 Characteristics of Surviving Participants in the Randomized, Controlled Trial of Postnatal Dexamethasone

 
Systolic blood pressure (SBP), diastolic blood pressure (DBP), and anthropometric measurements are presented in Table 2. Neither SBP nor DBP differed between dexamethasone-exposed and placebo groups. No differences were found when adjusted for exposure to antenatal steroids, the diagnosis of CLD, birth weight z value, maternal hypertension, race, or gender. No evidence was found of an interaction between dexamethasone exposure and the postmenstrual age at which treatment was initiated.


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  		TABLE 2 Blood Pressure and Anthropometric Measurements of School-Age Children Who Participated in a Randomized, Controlled Trial of Postnatal Dexamethasone

 
Figures 2 and 3 show z values for anthropometric measurements with 0 representing the 50th percentile for age and gender. There were no differences in height, weight, BMI, triceps skinfold, or mid-arm circumference between dexamethasone and placebo groups. No differences were found when adjusted for exposure to antenatal steroids, the diagnosis of CLD, maternal hypertension during pregnancy, birth weight z value, race, or gender.


Figure 2
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  		FIGURE 2 Z values for height, weight, and BMI of school-age children who participated in a randomized, controlled trial of postnatal dexamethasone.

 
In the total study sample, 20 of 68 participants had SBP and/or DBP ≥90th percentile with 11 of those ≥95th percentile based on oscillometric blood pressure standards for children.30 Twenty of 67 participants had BMI ≥85th percentile with 13 of those ≥95th percentile (overweight). Dexamethasone and placebo groups had similar frequencies of these outcomes.

Correlational Analysis
In the total sample, SBP and DBP were significantly related to height (Spearman's {rho} = 0.25 for both) but not weight or BMI. Separate analysis by treatment group revealed significant correlation, in the dexamethasone group, between SBP and weight, height, and mid-arm circumference (Spearman's {rho} = 0.33, 0.40, and 0.33, respectively), but no significant correlations were found in the placebo group.


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found no differences in growth or anthropometric measurements in school-age children who participated in a randomized, controlled trial of a 6-week tapering course of dexamethasone, given to VLBW neonates in the first and second months of life. Relative to blood pressure, the only group difference that we identified was the presence of the expected correlation of SBP to weight and height in the dexamethasone but not the placebo group.

It should be acknowledged that the current study, as well as previous studies, had relatively low power to detect a group difference as small as that reported by Doyle et al24 in their follow-up of children exposed to antenatal steroids (4 mmHg). Given our sample size, we had 80% power to detect differences in SBP of ≥8 mmHg. Clearly, smaller differences could be clinically significant, and it is possible that differences in blood pressure may become evident as these children mature. Regarding growth, our sample size was not adequate to detect differences <7 cm in height and 9 kg in weight.

Although our finding of no effect of postnatal dexamethasone on blood pressure is consistent with the findings of others,19,21,35 antenatal exposure to steroids has been associated with elevated blood pressure in later life both in animal experiments22,36,37 and in an observational study in humans.24 Posited explanations for the long-term effects of antenatal steroids on blood pressure include alterations in kidney development, such as reduced nephron number, and alterations in the developing renin-angiotensin system.37 The vulnerability of the kidney to steroid effects would be expected to be particularly high when its growth is most rapid, as is true between 22 to 34 weeks of gestation.38 After premature birth, nephron formation may be altered and may occur only for the first 40 days.39 We found no evidence of an interaction between postmenstrual age at treatment and dexamethasone effect on blood pressure.

Among the published studies17–19,21 of school-age children who, as neonates, were treated with dexamethasone, only 1 found an effect of dexamethasone on growth.21 However, the studies by Gross et al18 and Mieskonen et al17 involved only 17 and 16 dexamethasone recipients, respectively, and in the study by Jones et al,19 39% of neonates who were randomly assigned to placebo treatment were later treated with open-label dexamethasone. The small sample size17,18 and the contamination of the placebo group19 would have attenuated any potential group differences. In the trial by Yeh et al, 20 at 2 years of age, boys treated with dexamethasone had lower weight and height than controls, and at 8 years, children randomly assigned to dexamethasone were 3.5 cm shorter than controls.21 Differences between the study by Yeh et al20 and the current study include the timing and dose of dexamethasone treatment and the inclusion criteria. In the study by Yeh et al,20 dexamethasone treatment was initiated at <12 hours of age, as compared with 19 days in the current study. The neonates randomly assigned in the current study were at higher risk of CLD, as indicated by a prevalence of CLD, among placebo recipients, of 73% in the current study, as compared with 35% in the study by Yeh et al.20 Doyle et al11 have emphasized that, in randomized trials in which participants have a higher a priori risk of CLD, the direct effects of dexamethasone on brain development maybe attenuated by the indirect effects, mediated by improved pulmonary outcomes. Applying this argument to the current context, the putative effect of dexamethasone on growth (a slowing) could be attenuated because of an indirect effect (enhanced growth) mediated by a decreased risk of CLD.40–42

Of concern is that 16% of the children whom we studied had SBP and/or DBP ≥95th percentile based on age- and gender-specific oscillometric BP reference values. The Collaborative Dexamethasone Trial Follow Up Group reported that 16% of the participants had SBP >95th percentile at 13 to 17 years of age,19 and in cohort studies from England, Australia, the Netherlands, and the United States, an association has been observed between VLBW and higher blood pressure during adolescence and young adulthood (ages 15 to 20 years).24,43–45 Childhood blood pressure is predictive of blood pressure in adulthood,46,47 suggesting that VLBW children may be at increased risk for adult cardiovascular disease.

It is also concerning that 30% of the children whom we studied were at risk for overweight (ie, age- and gender-specific BMI ≥85th percentile), identical to the proportion in a recent study of a national probability sample of 6- to 11-year-old children.48 Overweight children are more likely to become overweight adults,49 increasing their risk of cardiovascular and metabolic disease. The risk of these adverse health states is influenced not only by BMI but also by the distribution of adiposity50 and the growth trajectory.51,52 Central adiposity is associated with an increased risk of hypertension and insulin resistance; and during infancy, prematurely born children have a greater proportion of central adiposity.53 Moving from a low BMI at 2 years of age into higher BMI percentiles at age 11 to 12 years has been associated with coronary heart disease and insulin resistance in adulthood.54,55 Because their BMI is typically low during infancy, VLBW children who exhibit catch-up growth typically have experienced a greater change in BMI during childhood than children born with normal birth weight, potentially increasing their risk for later health problems.

Several limitations of our study may have masked a difference between the 2 study groups, including the modest sample size and the proportion (28%) of the sample that we did not evaluate at follow-up. Nonetheless, this is the largest study of the long-term effects of dexamethasone from a randomized trial in which there was no dexamethasone treatment of participants randomly assigned to placebo. Relative to our finding that a large proportion of VLBW infants have elevated blood pressure, it should be noted that we used an oscillometric device, which tends to overestimate SBP when compared with auscultation. Further, there are no reference data available from the device (Alaris) that we used, so we compared our data with normative values obtained via another oscillometric monitor (Dinamap 8100). In addition, measurements of blood pressure made during 1 clinic visit are known to be less valid than measurements made on >1 visit29; and without ambulatory blood pressure monitoring, we cannot exclude the possibility that these children may have exhibited white coat hypertension (ie, a transiently elevated blood pressure in the presence of a medical professional). Finally, we did not assess sexual maturation, which is felt to be independently associated with blood pressure.56

Continued follow-up is needed for infants exposed to relatively high doses of dexamethasone during infancy, because manifestation of effects of this treatment on blood pressure might occur after childhood. Our study adds to the increasing body of evidence suggesting that former VLBW infants are at increased risk for elevated blood pressure at school age and young adulthood, implying a need for long-term surveillance for hypertension in this group.31 In addition, further research is needed on the effects of growth during infancy and childhood on health outcomes of adolescents and adults born with VLBW.


Figure 3
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  		FIGURE 3 Z values for triceps skinfold thickness and mid-arm circumference of school-age children who participated in a randomized, controlled trial of postnatal dexamethasone. DEX indicates dexamethasone; TST, triceps skinfold thickness; MAC, mid-arm circumference.

 


   ACKNOWLEDGMENTS
 
This research was supported by the General Clinical Research Center of Wake Forest University Baptist Medical Center grant M01-RR07122, National Institutes of Health grant P01 HD047584, the Intramural Research Support Committee of Wake Forest Medical School, and the Brenner Center for Child and Adolescent Health.

We thank Alice Scott, RN, Lori Cook, Peter Porcelli, MD, and the General Clinic Research Center staff for their assistance, and the parents and children for their participation.


   FOOTNOTES
 
Accepted May 25, 2006.

Address correspondence to Lisa Washburn, MD, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail: liwashbu{at}wfubmc.edu

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


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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