AN ANIMAL STUDY RAISES ADDITIONAL CONCERNS ABOUT THE USE OF A PARTICULAR STEROID ON PREMATURE INFANTS

Findings published in the January 2002 edition of American Journal of Physiology -- Regulatory, Integrative, and Comparative Physiology

Bethesda, MD (February 6, 2002)  -- New study results regarding the use of dexamethasone as a treatment for neonatal respiratory problems may add to existing concerns about the use of this steroid in premature infants.  An animal study, carried out by a team of physiologists from the University of Michigan, has demonstrated the long-term effects of dexamethasone on stress response and behavior later in life.

Background

Dexamethasone (dex) is a therapy that neonatologists use because it improves the function of premature infants' lungs and consequently allows them to be removed from a ventilator more quickly.  Although steroids have been used to treat ventilator-dependent premature infants who were developing chronic lung disease at one month of age, they have recently been used much earlier in an attempt to prevent chronic lung disease.

In January 2001, the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network announced research findings stating that dexamethasone, a treatment commonly prescribed to reduce the risk of chronic lung disease in extremely premature infants, did not reduce the risk of death or chronic lung disease in these infants and may increase the risk for perforation of the intestines. 

Two years earlier, the New England Journal of Medicine presented another research finding contending that infants treated with dexamethasone at two weeks of age had an infection rate that was 50 percent higher than the infants who received placebo at two weeks of age. Moreover, both groups of infants gained weight more slowly and had slower head growth while they received dexamethasone.

The Study

A study conducted at the University of Michigan was designed to develop a rat model system in which to study long-term effects of a prolonged, tapering course of neonatal dex administration.  Unlike other studies, where single doses of dex were given at particular postnatal ages, the objectives of this study were twofold: (1) to provide dex during a postnatal age in the rat that corresponds to the neurodevelopmental time point at which human premature infants receive prolonged dex therapy and (2) to provide dex in tapering doses (between third and sixth day after birth). The specific goal of the model was to more closely mimic glucocorticoid protocols provided in the neonatal intensive care setting where six-week courses are still administered.

The authors of "Effects of Tapering Neonatal Dexamethasone On Rat Growth, Neurodevelopment, and Stress Response," are Shelly B. Flagel, Delia M. Vazquez, Stanley J. Watson, Jr., and Charles R. Neal, Jr., all from the University of Michigan, Ann Arbor, MI.   Their findings are published in the January 2002 edition of American Journal of Physiology -- Regulatory, Integrative, and Comparative Physiology. 

Methodology

Adult Sprague-Dawley rats were housed in our animal unit and maintained in accordance with federal guidelines on the care and use of laboratory animals. All animals were kept under constant temperature and  light-dark cycle, and they were provided with food and water, as desired. With the use of a trio mating system (2 females: 1 male), 20 female rats were mated. Females were then housed in pairs until estimated gestational day 18, at which point they were housed individually.

The day of birth was designated PD 1. On PD 2, each litter was sexed and culled to 12 pups (six males, six females) to ensure equality in nutrition and maternal care within litters. Pups were separated into three treatment groups on PD 3, with each group represented within one litter, to control for variations in maternal behavior. On PD 8, a male and a female pup from each treatment group were eliminated in order to reduce the litter size to six animals for the remainder of the study.

Each litter was assigned to three treatment groups: handled controls (Han), saline injected animals (Veh), and Dex-treated animals (Dex). All pups within each litter were removed from their mother and treated or handled for a period of five minutes. Animals in the dex group received an intramuscular injection of dex in tapering doses on PD 3 through PD 6.  Animals in the Veh group received equivalent volumes of intramuscular sterile saline as the dex animals, and animals in the Han group received no injection but were handled during the same time period on PD 3 through 6.

The animals were monitored for:

Measurements. Weight and length were recorded before handling or injection on PD 3-6, 8, 14, and 20 for each treatment group.

Behavioral testing:  On PD 21, open-field behavior was assessed.

Adrenocortical response to novelty stress. On PD 33, blood sampling was performed via the tail nick method at 15, 30, 60, and 120 min following exposure to the preference box, with a basal time point obtained before the procedure.

Brain weights. Brain weights were obtained during necropsy on PD 8, 23, and 35.

Body weight, length, rate of growth, brain weight, hormonal values, and behavioral data were averaged across treatment groups.

Results

Somatic (skeletal) growth and brain weight was decreased in dexamethasone-treated animals.  Dexamethasone-treated animals also demonstrated delays in gross neurological development on PD 7 and 14 but not PD 20. In late adolescence (PD 33), dexamethasone-treated animals were less active in light and dark environments, while demonstrating a blunted serum corticosterone (the principal glucocortoid in the rat) response to a novel stress.

Conclusions

Given that adequate glucocorticoid activation is vital for learning memory acquisition and is dependent on optimal exposure to elevated glucocorticoid levels, the results of this present study should raise concern with regards to the neurodevelopmental repercussions a prolonged steroid course may have on the premature human infant.

Therefore, this news research finds the dissociation between behavioral and hormonal stress responsiveness resulting from dexamethasone exposure permanently alters central nervous system function, particularly within the neuroendocrine stress axis. This may lead to increased risk for learning impairment.

Source: January 2002 edition of American Journal of Physiology - Regulatory, Integrative, and Comparative Physiology.

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: To set up an interview with a member of the research team, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.