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PEDIATRICS Vol. 110 No. 2 August 2002, pp. 275-279

Association of Antenatal and Postnatal Dexamethasone Exposure With Outcomes in Extremely Low Birth Weight Neonates

Judy L. LeFlore, NNP, PhD*, Walid A. Salhab, MD{ddagger}, R. Sue Broyles, MD{ddagger} and William D. Engle, MD{ddagger}

* Children’s Medical Center of Dallas, Dallas, Texas
{ddagger} Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background. Recent studies of preterm neonates have indicated that antenatal dexamethasone (ADX) may have adverse effects on cranial ultrasound findings at the time of hospital discharge, including periventricular leukomalacia. Furthermore, both ADX and postnatal dexamethasone (PDX) may have adverse effects on subsequent neurodevelopmental outcome.

Objectives. 1) To assess the effects of ADX exposure on cranial ultrasound findings at the time of hospital discharge and 2) to evaluate the individual effects of ADX and/or PDX exposure on subsequent neurodevelopmental outcome in extremely low birth weight (ELBW) neonates in whom confounding risk factors known to influence outcome were controlled.

Methods. One hundred seventy-three ELBW (≤1000 g) neonates were studied using a prospectively collected database and hospital and clinic records. Study patients were assigned to 1 of 4 groups according to dexamethasone exposure: group I, no dexamethasone exposure; group II, ADX exposure to hasten fetal lung maturity; group III, PDX exposure for chronic lung disease; group IV, both ADX and PDX exposure. The 4 groups were compared using multinomial logistic regression or analysis of covariance to control for confounding variables. Primary outcome variables were cranial ultrasound findings at hospital discharge and results of developmental testing at 18 to 22 months’ corrected age (Bayley Scales of Infant Development).

Results. Cranial ultrasound results as well as Bayley Scales of Infant Development scores were similar in groups I and II and in groups III and IV. The likelihood of abnormal cranial ultrasound studies and lower scores on neurodevelopmental testing was greater in groups III and IV versus groups I and II. In this study, ADX did not seem to increase the risk of periventricular leukomalacia.

Conclusions. ADX exposure is not associated with an increase in abnormal cranial ultrasound findings in ELBW neonates. PDX exposure, but not ADX exposure, is associated with worse neurodevelopmental outcome in this population. These results are supportive of the recent statement by the American Academy of Pediatrics (Committee on Fetus and Newborn) and the Canadian Paediatric Society (Fetus and Newborn Committee) and emphasize that PDX should be used with caution in ELBW neonates.

Key Words: preterm neonate • corticosteroids • chronic lung disease • neurodevelopment • analysis of variance • ANCOVA • multinomial regression • Bayley • head ultrasound

Abbreviations: ADX, antenatal dexamethasone • RDS, respiratory distress syndrome • PDX, postnatal dexamethasone • CLD, chronic lung disease • ELBW, extremely low birth weight • PVL, periventricular leukomalacia • BSID II, Bayley Scales of Infant Development • MDI, mental development index • PDI, psychomotor development index


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The use of dexamethasone in the high-risk fetus and neonate is common; while antenatal dexamethasone (ADX) exposure reduces the risk of respiratory distress syndrome (RDS), intracranial hemorrhage, necrotizing enterocolitis, nonoliguric hyperkalemia, and neonatal death, postnatal dexamethasone (PDX) therapy improves lung function and facilitates successful extubation in infants with chronic lung disease (CLD).1–3 However, recent data regarding the vulnerability of the developing central nervous system to the effects of dexamethasone have raised concerns regarding its safety in preterm neonates, particularly in those with extremely low birthweight (ELBW; ≤1000g).4,5 Baud et al6 reported that cranial ultrasound findings consistent with periventricular leukomalacia (PVL) were more likely with ADX exposure compared with exposure to betamethasone. Furthermore, PDX given to infants with CLD has been linked to an increased incidence of cerebral palsy and low scores on both the mental and psychomotor components of the Bayley Scales of Infant Development (BSID II).7–9 The National Institute of Child Health and Human Development collaborative trial demonstrated that infants born to mothers who received a complete course of betamethasone or dexamethasone were less likely to have significant intracranial hemorrhage10; however, no differences in neurodevelopmental outcome have been noted between infants whose mothers were treated and those whose mothers did not receive antenatal corticosteroids. Nevertheless, the possibility that exposure to both ADX and PDX may have additive effects on either cranial ultrasound findings or neurodevelopmental outcome has not been established.

Reports of adverse neurodevelopmental outcome in preterm neonates range from 9% to 49%,7–9,11 and ELBW neonates are at higher risk for adverse neurodevelopmental outcome than preterm infants in other birth weight categories.11 Multiple antenatal and postnatal risk factors seem to contribute to adverse neurologic outcome in this group; however, determining the role of an individual risk factor is difficult. Furthermore, in many of the studies reported, identification and/or control of these risk factors is incomplete, and commonly used therapies beneficial for one organ system may be deleterious for another, such as the central nervous system.12–15

The objectives of this study were 1) to assess the effects of ADX exposure on cranial ultrasound findings at the time of hospital discharge in ELBW neonates and 2) to evaluate the individual effects of ADX and/or PDX exposure on subsequent neurodevelopmental outcome in ELBW neonates in whom confounding risk factors known to influence outcome were controlled.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study population was identified using a prospectively collected, previously validated computerized database.16 All live-born neonates with birth weight ≤1000 g born between January 1, 1995, and December 31, 1997, at Parkland Memorial Hospital were eligible for inclusion in the study. During the study period, 307 ELBW neonates were born, and 174 (57%) survived until discharge. Of the 133 infants who expired, 79 (59%) lived ≤24 hours, and 121 (91%) survived ≤2 weeks. Birth weight was <750 g in 93 (70%), and 66 (50%) were males.

Complete maternal and neonatal hospital records and follow-up clinic records with results of formal neurodevelopmental testing at 18 to 22 months’ corrected age were available for 173 (99%) of the surviving neonates. Maternal and neonatal medical records were reviewed and the data abstracted by a single reviewer (J.L.L.). Maternal variables abstracted were last school grade completed, mode of delivery, placental abruption, chorioamnionitis (temperature ≥38°C during labor), and ADX administration including number of doses and courses. ADX was given at the discretion of the attending obstetrician using previously described guidelines17; the most frequent reason for not initiating ADX was anticipated imminent delivery. The ADX dosing schedule was four 5-mg doses given intramuscular every 12 hours.

Neonatal data abstracted included gender, race, birth weight, gestational age, Apgar score at 5 minutes, umbilical artery pH and pCO2, intrauterine growth assessment, RDS, sepsis (blood and/or cerebral spinal fluid culture positive), definite necrotizing enterocolitis, number of days of mechanical ventilation, number of days requiring supplemental oxygen, postconceptional age supplemental oxygen was discontinued, cranial ultrasound results in the first week of life and at discharge, length of stay, and PDX administration including day of life initiated. PDX administration was at the discretion of the attending neonatologist caring for the neonate; generally a starting dose of 0.3 to 0.5 mg/kg was given, and tapering occurred over a 14- to 42-day period. Infants who received only brief courses (1–2 days) of dexamethasone for suspected airway edema and/or to facilitate planned extubation were not included in a PDX group (see below).

Infants were examined periodically after hospital discharge in the Low Birthweight Clinic at Children’s Medical Center of Dallas, and formal neurodevelopmental testing was conducted at a corrected age of 18 to 22 months. Data abstracted from the Low Birthweight Clinic records included the BSID II, which included the mental scale (mental development index [MDI]) and the psychomotor scale (psychomotor development index [PDI]), performed by a certified examiner experienced in the BSID II test procedures.

Each of the 173 study patients was assigned to 1 of 4 groups according to dexamethasone exposure: group I, no dexamethasone exposure (n = 38); group II, ADX exposure to hasten fetal lung maturity (n = 71); group III, PDX exposure for CLD (n = 15); and group IV, both ADX and PDX exposure (n = 49). Primary outcome variables were cranial ultrasound findings at hospital discharge and results of BSID II testing. Cranial ultrasounds (Acuson 128 IP/10, Mountain View, CA) were performed routinely on day 3, between days 7 to 10, and just before hospital discharge; additional studies were obtained as clinically indicated. The studies were interpreted by pediatric radiologists unaware of the patients group assignments. The severity of intracranial hemorrhage was determined using the 4-level grading system described by Papile et al.18 The BSID II was performed by a certified examiner masked to group assignment.

Data were analyzed (SPSS 9 for Windows, SPSS, Inc, Chicago, IL) using descriptive, parametric, and nonparametric statistics according to the level of data obtained and the examination of the assumptions underlying the tests. Univariate analyses were performed to assess the distribution and variability of the data and to describe the sample.19 To examine equal distribution of potential confounding variables among the groups, analysis of variance was used for continuous variables and {chi}2 for dichotomous variables. Logistic regression and multiple regression were used to evaluate the predictive value of variables found to be significantly different among the groups. Although a marginally significant difference in gender, chorioamnionitis, and route of delivery existed among the groups, these variables were not shown to have predictive value and thus were not used in the final model. In addition, other variables commonly associated with differences in outcome (eg, gestational age) were evaluated as potential confounders. After a direct linear relationship was confirmed, the 4 groups were compared using multinomial logistic regression or analysis of covariance to control for final variables shown to predict the primary outcomes; these variables were duration of oxygen therapy, duration of mechanical ventilation, and length of stay. The Bonferroni correction was used for multiple comparisons. All values are expressed as mean ± standard deviation of the mean unless otherwise indicated. The median is reported when a distribution was highly skewed, and significance was assessed by the Kruskal-Wallis test. {alpha} and ß were set at 0.05 and 0.20, respectively.

This study was approved by the Human Subjects Review Boards at University of Texas Southwestern Medical Center at Dallas and Parkland Health and Hospital System.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
As shown in Table 1, birth weight, gestational age, and ethnicity were similar among groups. The female:male proportion was greater in groups I and II versus groups III and IV (P = .04), and cesarean delivery was more frequent in group I compared with the other 3 groups (P = .03). Maternal chorioamnionitis was more frequent in groups I and II versus III and IV (P = .05). There were no differences in maternal educational status among the groups. Frequency of placental abruption, Apgar score at 5 minutes ≤5, and umbilical artery pH <7.1 were similar among the groups, as were median values for umbilical artery PCO2. There were no differences observed in the number of ADX doses given to the mothers of infants in group II (2.9 ± 1.9) versus group IV (3.2 ± 1.6; P = .43). A single dose of ADX was given to 14/71 (19.7%) mothers of group II infants and 3/49 (6.1%) mothers of group IV infants (P = .08). Eight of the 120 mothers of group II and IV neonates (5 and 3, respectively) received 2 courses of dexamethasone.


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  		TABLE 1. Demographic Characteristics of Study Neonates

 
The percentage of infants diagnosed with RDS and requiring surfactant replacement therapy was similar among the groups (Table 2). The number of days intubated, number of days receiving supplemental oxygen therapy, postconceptional age when supplemental oxygen therapy was discontinued, and length of stay were greater in groups III and IV versus groups I and II. There were no differences in the postnatal age at which PDX therapy was initiated between groups III (30 ± 14 days) versus group IV (25 ± 10 days; P = .17). More infants in groups I and II had necrotizing enterocolitis; however, this difference did not achieve statistical significance (Table 2).


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  		TABLE 2. Clinical Characteristics of Study Neonates

 
The results of cranial ultrasound studies at hospital discharge are shown in Table 3. The likelihood of having an abnormal cranial ultrasound study at hospital discharge was greater in ELBW neonates who received PDX alone (group III) or both PDX and ADX (group IV) compared with the likelihood in groups I and II (P <.01); however, no significant differences between groups III and IV were noted. The percentage of infants with cystic PVL was similar in those whose only dexamethasone exposure was antenatal (group II, 4%) versus those with no dexamethasone exposure (group I, 5%) or no ADX exposure (groups I and III combined, n = 53, 4%). This latter percentage was lower than that observed in infants with any ADX exposure (groups II and IV combined, n = 120, 8%); however, the difference was not statistically significant by {chi}2 (P = .44). Furthermore, the {phi} coefficient of association (0.047) indicated no linear association between ADX exposure and cystic PVL (P = .57). When the discharge cranial ultrasound revealed either cystic PVL or increased periventricular echogenicity without cystic changes, the incidence was 16%, 7%, 40%, and 20% in groups I through IV, respectively (P = .009).


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  		TABLE 3. Cranial Ultrasound and Neurodevelopmental Outcomes

 
Bayley psychomotor and mental scores at 18 to 22 months were low in ELBW neonates who were exposed to PDX alone (group III: MDI, 73 ± 13; PDI, 74 ± 11) or to both PDX and ADX (group IV: MDI, 74 ± 13; PDI, 76 ± 15; Table 3). Furthermore, no differences in MDI and PDI scores were observed between groups III and IV (power = 0.80). When groups III and IV were combined, there was a significant inverse relationship noted between duration of PDX and both MDI and PDI (r = –0.45, P =.001 and r = –0.28, P = .03, respectively). Neurodevelopmental outcomes for those exposed to ADX alone (group II: MDI, 85 ± 12; PDI, 89 ± 12) were similar to those observed in neonates with no dexamethasone exposure (group I: MDI, 82 ± 13; PDI, 87 ± 13, power = 0.80), and both of these groups had improved outcomes relative to groups III and IV. Cranial ultrasound results at hospital discharge (Table 3) did not predict independently either MDI on PDI scores at 18 to 22 months’ corrected age.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In a recently reported systematic review of PDX therapy for prevention or treatment of CLD, Barrington20,21 identified 8 controlled studies (679 neonates) in which neurodevelopmental outcome was reported. Many of the studies, were "contaminated" ie, "control" infants who later received dexamethasone were included. In addition, these studies included relatively more mature infants with birth weight as great as 1500 g in 7 of the studies, and the postnatal age at which dexamethasone was given varied from soon after birth to ~2 weeks. Conversely, we studied the group which seems to be at highest risk of poor outcome, ie, those with birth weight ≤1000g, and to our knowledge, this is the largest study to date which focuses on the effects of dexamethasone exposure on outcome only in this group. In addition, there was no "contamination" of groups; infants either were exposed to no dexamethasone, antenatal or postnatal exposure only, or both antenatal and postnatal exposure. Furthermore, infants in the current study were more likely to receive dexamethasone at a later postnatal age than those infants included in the report by Barrington (Table 2).20

The conclusions of this study are in agreement with the findings of Barrington and other investigators,5,7–9,11 ie, PDX is associated with worse neurodevelopmental outcome in preterm neonates. These studies of human neonates are in agreement with animal studies in which adverse effects on brain growth have been linked to dexamethasone exposure.4,22–26 Obviously, if patients with CLD are those who are most likely to receive PDX, there might be a number of variables related to CLD (eg, length of hospitalization, need for mechanical ventilation, etc), which also could affect neurodevelopmental outcome. In the present study, a rigorous process of controlling for confounding variables was undertaken. After this process, PDX exposure remained as a significant predictor of poor outcome at 18 to 22 months’ corrected age. This association was apparent despite the higher incidence of chorioamnionitis, a significant risk factor for the development of cerebral palsy, 27–32 in the groups not exposed to PDX (groups I and II), and despite the relatively late PDX exposure in our population (Table 2).

If perinatal dexamethasone exposure impairs normal brain growth, one might expect ADX exposure to exert a particularly detrimental effect on outcome, because the exposure occurs at an earlier point in time (compared with postnatal exposure) when the developing central nervous system is presumably even more vulnerable. The study by Baud et al6 is of particular concern in its finding that preterm infants exposed to ADX were more likely to develop PVL than those exposed to antenatal betamethasone. In that study, the difference in PVL between those with ADX exposure and those with no antenatal steroid exposure was not significant; however, the adjusted odds ratio was 1.5 (95% confidence interval: 0.8–2.9). In the current study, ELBW neonates whose only dexamethasone exposure was antenatal (group II) had a similar incidence of cystic PVL compared with those with no dexamethasone exposure (group I; 4% vs 5%, respectively); in addition, there was no difference in the incidence of cystic PVL between those who were exposed to ADX (groups II and IV) and those who were not exposed to ADX (groups I and III; 8% vs 4%, respectively). The difference between the incidence of cystic PVL in group III (0%) versus group IV (14%) was not statistically significant; however, it should be noted that the overall number of infants with cystic PVL in this study was small (12/173, 7%), and thus we are unable to be conclusive regarding this relationship. However, our results are not supportive of the findings of Baud et al suggesting that ADX and PVL may be associated.6 Furthermore, when the discharge diagnosis included either increased periventricular echogenicity or cystic PVL, the incidence was lowest (7%) in those whose dexamethasone exposure was only antenatal (group II). It should be noted that relatively few mothers (8/120) of neonates in the current study received >1 course of ADX, thus we were unable to assess the effects of multiple courses of ADX, a recent cause of concern regarding poor outcome.22–23

A primary goal of this study was to determine the effects, if any, of ADX and PDX on outcome, and to determine whether an additive effect exists. We found that those ELBW neonates exposed to ADX (group II) had outcomes on the BSID II evaluations that were similar to those in infants with no dexamethasone exposure (group I). Furthermore, infants who received both ADX and PDX (group IV) had outcomes (BSID II) which were similar to, but not worse than, those observed in infants who received only PDX (group III). These results argue against a detrimental effect of ADX on outcome at 18 to 22 months, but clearly are supportive of previous studies indicating an adverse effect of PDX on neurodevelopmental outcome.9

The findings of this study are subject to the limitations of a retrospective analysis. Nevertheless, we are confident that the large sample size and the statistical methods used to control for confounding variables allow us to reach the following conclusions regarding dexamethasone use in ELBW neonates: 1) ADX is not associated with an increased incidence of PVL or worse neurodevelopmental outcome, and 2) PDX is associated with worse neurodevelopmental outcome and should be used with extreme caution, as suggested by others, most recently the American Academy of Pediatrics/Canadian Paediatric Society.33


   ACKNOWLEDGMENTS
 
This study was supported by a grant from Sigma Theta Tau.


   FOOTNOTES
 
Received for publication Aug 30, 2001; Accepted Mar 11, 2001.

Reprint requests to (W.D.E) University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9063. E-mail: william.engle{at}utsouthwestern.edu

This study was presented, in part, at the Pediatric Academic Societies Meeting, Baltimore, MD, April 30, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics



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M. E. George, V. Sharma, J. Jacobson, S. Simon, and A. J. Nopper
Adverse Effects of Systemic Glucocorticosteroid Therapy in Infants With Hemangiomas
Arch Dermatol, August 1, 2004; 140(8): 963 - 969.
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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. R. Neal Jr., G. Weidemann, M. Kabbaj, and D. M. Vazquez
Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R375 - R385.
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