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Early Exposure To A Tapering Dose Of Dexamethasone Has Long-Lasting Effects On  Neurodevelopment And Neuroendocrine Function

An animal study finds dangerous consequences of a drug used for treating extremely low birth weight infants with respiratory disorders

(June 28, 2004) -- Bethesda, MD -- Any parent of a newborn with extremely low birth weight (ELBW) faces the possibility that their child will be diagnosed with severe respiratory distress syndrome, which results in ventilator and/or oxygen dependency, and subsequent onset of chronic lung disease. Until recently, early administration of a prolonged course of postnatal dexamethasone was recommended to decrease the pulmonary inflammatory process during the early neonatal period.  This approach changed, however, following a Taiwanese study that demonstrated a significant increase in neurodevelopmental dysfunction in neonates treated with dexamethasone. 

Background

The Taiwanese conclusions were reached within the context that the window of exposure to dexamethasone in critically ill ELBW infants spans an extensive period of perinatal viability, ranging from 24 to 40 weeks post-conception.  It is during this time that the human brain undergoes significant structural and functional transformations, thereby making it particularly vulnerable to external influences. 

Clinical studies examining acute dexamethasone effects on physiology and central nervous system function in premature infants have been limited.  Past research into premature infants who received prolonged dexamethasone therapy experience reduced linear growth, decreased weight gain, and smaller head circumferences. During the acute phase of dexamethasone exposure, changes in gross neuromotor function have also been noted. As a result, use of dexamethasone to improve pulmonary function in ventilator-dependent ELBW infants is undergoing significant modification towards more judicious treatment – dexamethasone therapy is given less often and shorter courses are now used.

The concern remains that little is known about dexamethasone effects on long-term neurodevelopment.  For obvious reasons, human testing is not desired. Researchers have previously developed a rat model where newborn pups are exposed to tapering doses of dexamethasone at time points corresponding to the neurodevelopmental age when human infants are traditionally exposed to this drug in the neonatal intensive care unit.  This model was recently used to demonstrate an association between dexamethasone exposure in the neonatal rat pup and changes in LHPA function in the adolescent, including increased anxiousness in the light-dark test of anxiety and, in response to a mild novelty stress, a blunted corticosterone response.  However, the findings from this research could not establish if these alterations were permanent.

A New Study

A new study sought to test whether effects of neonatal dexamethasone exposure on LHPA axis function persist to adulthood.  The authors of the study, entitled “Effect of Neonatal Dexamethasone Exposure on Growth and Neurological Development in the Adult Rat,” are Charles R. Neal, Jr. and Delia M. Vázquez, both with the Mental Health Research Institute and Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, MI; Gabrielle Weidemann, Department of Psychology, University of New South Wales, Sydney, Australia; and Mohamed Kabbaj, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL. Their findings appear in the online edition of the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. The journal is one of 14 published monthly by the American Physiological Society (www.the-aps.org). 

Methodology

This study is different than previous research in this topic area because the methodology incorporates a tapering dose of dexamethasone during a postnatal age in the rat that corresponds to the neurodevelopmental time point at which human premature infants have historically received prolonged glucocorticoid therapy for chronic lung disease. This is in contrast to animal models that use short courses or single doses of dexamethasone.

Using a within-litter design, 12 pups were assigned to one of three groups on postnatal day 2 (P2).  The groups were designated either “handled controls,” “saline-injected controls,” or “animals receiving dexamethasone between days P3 and P6.” 

Measures used to examine neonatal neurodevelopment included posture, righting reflex, postural flexion and extension, vibrissa placing, forelimb and hindlimb placing, geotaxis and bar hold.  Physical maturity was measured by observing eye and ear opening, ear folding, fur development and tooth eruption.

Results

The research findings suggest that prolonged exposure to dexamethasone during the neonatal period may have long-lasting consequences.  Conclusions reached were:

• Animal housing:  The research team observed slow termination in the LHPA stress response and anxious behavior in open field testing, raising the possibility of dexamethasone exposure creating a vulnerable state in the animal, leading to alterations in LHPA function only after experiencing what could be construed as prolonged social isolation.

• Somatic and brain growth:  A regimen of decreasing dexamethasone exposure early in life has a lasting impact on the body’s growth.  The researchers observed decreased somatic growth observed in the dexamethasone-treated pups attributed to the drug’s direct effects on catabolism and tissue accretion.  Dexamethasone-treated animals were also found to have decreased gross brain weights. When corrected for variations in somatic weight, brain weights did not differ between groups in males, but were still lower in females.

• Neurodevelopment and physical maturation:  Dexamethasone-treated animals experienced transient variations in neurodevelopment and physical maturation when compared to controls. However, no gross neurological deficits were observed in the dexamethasone-treated pups by day P20, suggesting that the pathways relevant to organization of reflexes and behavior assessed on the exam were developing normally by the time of weaning. Primitive reflexes appear and disappear in defined sequences during development, with an absence or persistence of any reflex beyond expected time of extinction typically indicating significant brain dysfunction.

• Measures of Stress Reactivity:  In this study, increased anxiety-like behaviors were observed in single-housed DEX animals in the elevated plus maze and open field, but there were no differences between groups in a light-dark test. Although these animals exhibit increased anxiety-like behavior in threatening environments, they demonstrate no such behavior when placed in a less threatening novel environment.

Conclusions

This study finds that an early exposure to a tapering dose of dexamethasone has long-lasting effects on neurodevelopment and neuroendocrine function in the male rat. These findings raise concerns about maladaptive behavioral strategies that may be subtle and not recognizable until later in development. Such effects may have important implications on learning, mood and ultimately quality of life in survivors of prematurity.

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Source: Online edition of the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. The journal is one of 14 published monthly by the American Physiological Society (www.the-aps.org). 

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: A copy of the research article is available in pdf format to the press. Members of the press are invited to obtain a pdf copy of the study and to interview members of the research team. To do so, please contact Donna Krupa at (301) 634-7209 (direct dial), (703) 967-2751 (cell) or dkrupa@the-aps.org.