Perinatal treatment with glucocorticoids and the risk of maldevelopment of the brain

Benešová, O; Pavlík, A

doi:10.1016/0028-3908(89)90073-7

Cited by 110 publications

(69 citation statements)

References 23 publications

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“…Dexamethasone is a known teratogen and fetotoxicant (27)(28)(29)(30)(31)(32)(33)(34). We observed that at a maternal dose of 15 mg/kg of dexamethasone, embryos from Ahr Ϫ/Ϫ dams exhibited a 9-fold higher level of mortality than those from Ahr ϩ/ϩ dams (p Ͻ 0.0006, Fig.…”

Section: Resultsmentioning

confidence: 81%

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Thomae

Glover

Bradfield

2004

Journal of Biological Chemistry

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The aryl hydrocarbon receptor (encoded by the Ahr locus) is a ligand-activated transcription factor that mediates the toxicology and teratology of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin). In an effort to understand the role of the maternal compartment in dioxin teratology, we designed a breeding strategy that allowed us to compare the teratogenic response in embryos from Ahr ؊/؊ (null) and Ahr ؉/؉ (wild-type) dams. Using this strategy, we demonstrate that embryos from the Ahr ؊/؊ dams are 5-fold more sensitive to dioxin-induced cleft palate and hydronephrosis as compared with embryos from an Ahr ؉/؉ dam. Moreover, this increased teratogenic sensitivity extends beyond dioxin, because embryos from Ahr ؊/؊ dams exhibited a 9-fold increase in their sensitivity to the fetotoxic effects of the glucocorticoid, dexamethasone. In searching for an explanation for this increased sensitivity, we found that more dioxin and dexamethasone reached the embryos from Ahr ؊/؊ dams as compared with embryos from Ahr ؉/؉ dams. We propose that increased deposition of teratogens/fetotoxicants to the embryonic compartment is the result of porto-systemic shunting and/or blocked P4501A induction in Ahr ؊/؊ dams. In addition to demonstrating the importance of maternal AHR in teratogenesis, these data may have implications that reach beyond the mechanism of action of dioxin. In this regard, the Ahr ؊/؊ mouse may provide a system that allows pharmacological agents and toxicants to be more easily studied in a model where first pass clearance is a significant obstacle.Chemical teratogens can perturb normal mammalian development through direct action on the embryo, indirectly through maternal toxicity, or as the result of a combination of both of these mechanisms. The maternal compartment can afford protection by functioning as a metabolic or physical barrier that reduces embryonic exposure to a given agent (1). The maternal compartment also holds the potential to serve as a site of teratogen bioactivation and may serve to increase the concentrations of active metabolites that directly perturb normal embryonic development (2, 3). Understanding the relative contributions of maternal and embryonic physiology for a given teratogen can be difficult, especially when chemical agents induce a variety of teratogenic end points or display remarkable pharmacological potency.One approach to understanding the relative contributions of the maternal and embryonic physiology is to define these two compartments via their respective genotypes. Such an approach is particularly powerful when working with null alleles that have been generated via gene targeting. In such cases, the dominance order is clear, as is the functional relationship between one or two copies of the wild-type allele. Through appropriate genetic crosses one can then generate informative combinations of maternal and embryonic genotypes that can help identify when maternally or embryonically expressed loci play a differential role in the teratogenic response to a specific chemical (4).Based...

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Section: Resultsmentioning

confidence: 81%

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Thomae

Glover

Bradfield

2004

Journal of Biological Chemistry

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“…Earlier studies with animals found a variety of alterations in neurobehavioral outcome following PNS exposure (Benesova & Pavlik, 1989;Meaney & Stewart, 1981;Weichsel, 1977). Studies on sheep found that greater exposure to early steroid decreased fetal growth (Jobe, Wadda, Berry, Ikegami, & Ervin 1998).…”

Section: Review Of the Literaturementioning

confidence: 99%

“…Social deficits after steroid treatment were a concern of the 1994 NIH consensus panel that set limits on antenatal steroid dosing, warning that long-term studies were needed because of findings in earlier steroid studies in small animals (Benesova & Pavlik, 1989;Meaney & Stewart, 1981).…”

Section: Pns and Social Outcomesmentioning

confidence: 99%

“…They were used to aid in decreasing infant dependence on ventilators and on oxygen (Halliday & Ehrenkranz, 2001a, 2001b. At school-age follow-up, preterm infants whose chronic lung disease was treated with long-term steroid tapering doses were identified to have poor neurodevelopmental outcomes (Yeh et al, 2004).Earlier studies with animals found a variety of alterations in neurobehavioral outcome following PNS exposure (Benesova & Pavlik, 1989;Meaney & Stewart, 1981;Weichsel, 1977). Studies on sheep found that greater exposure to early steroid decreased fetal growth (Jobe, Wadda, Berry, Ikegami, & Ervin 1998).…”

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confidence: 99%

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Cumulative Perinatal Steroids: Child Development of Preterm Infants

Purdy

Wiley

Smith

et al. 2008

Journal of Pediatric Nursing

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The development of premature infants may be altered due to exposure to high cumulative doses of the perinatal corticosteroid dexamethasone during critical growth periods. To compare child behavioral development of prematurely born infants who were exposed to higher perinatal steroids (PNS; N0.2 mg/kg) with that of infants exposed to lower PNS (≤0.2 mg/kg), we used the Vineland Adaptive Behavioral Scales to assess school-age behavioral outcomes of a historical cohort of 45 prematurely born infants. Children who had received higher PNS treatment were more likely to have lower overall behavioral developmental scores, especially lower social skills (p < .05). Higher PNS plus higher severity of illness during the first day of life based on the Clinical Risk Index for Babies (p = .016) and lower birth head size (p = .015) were linked with poorer behavioral outcomes among participants. Nursing practice includes promotion of quality care and should include closer evaluation of cumulative steroid therapy, severity of illness, and promotion of long-term follow-up support for premature infants. KeywordsPerinatal steroids; Dexamethasone; Preterm infants; Neurodevelopment PRETERM DELIVERY, ESTIMATED to occur in 7-11% of all North American births, is responsible for 75% of neonatal deaths (National Institutes of Health [NIH] Consensus Development Conference Statement, 1994). The outcomes of preterm infant survival are often dependent upon the provision of high-quality perinatal care, prior to 40 weeks' postconceptual age, as this is a vulnerable time in development. Over the past 30 years, synthetic or exogenous steroids have increasingly been prescribed before and after birth with the intent to improve infant lung maturity and outcomes. The 1994 NIH consensus panel recommendation for antenatal steroids (before birth) consisted of two doses of 12 mg of betamethasone given intramuscularly at 24-hour intervals or four doses of 6 mg of dexamethasone given intramuscularly at 12-hour intervals. In 2000, the panel revisited this recommendation and discouraged the use of multiple-course antenatal steroids because studies identified associations between steroids and impaired infant head growth and neurodevelop-mental outcomes (National Institutes of Health, 2000 Although commonly given for a variety of therapeutic reasons in perinatal care, the risks may not outweigh the benefits of either higher antenatal or postnatal steroid exposure. Perinatal steroids (PNS) are primarily administered for the promotion of infant lung maturation and reduction of respiratory distress syndrome and mortality (Huang, Dunlop, & Harper, 1999). Many premature infants have received multiple doses of therapeutic steroid drugs while in utero as well as in the postnatal period.Studies have retrospectively examined either antenatal or postnatal steroid effects . This study was the first to retrospectively identify the precise milligram amount of cumulative PNS dosed prior to 40 weeks and prospectively examine relationships with neurodevelopment of pre...

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“…The more preders and autoimmune diseases such as multiple sclerosis (24), renal calcification (25), abnormal lung mature the infant, the smaller and more abnormal the brain will be (5). Adult cardiovascular disease, underdevelopment (26), and neurological and behavioral deficits (27,28). developed kidneys, and diabetes were further linked to low birthweight (7).…”

Section: Helen Harrisonmentioning

confidence: 99%

Preemies On Steroids: A New Iatrogenic Disaster?

Harrison¹

2001

Birth

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Perinatal treatment with glucocorticoids and the risk of maldevelopment of the brain

Cited by 110 publications

References 23 publications

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

A Maternal Ahr Null Genotype Sensitizes Embryos to Chemical Teratogenesis

Cumulative Perinatal Steroids: Child Development of Preterm Infants

Preemies On Steroids: A New Iatrogenic Disaster?

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