TERIS
Summary
TERIS Agent Number: 1643 Bibliographic
Search Date: 08/07
Agent Name: DEXAMETHASONE Review
Date: 02/08
Dexamethasone is a synthetic corticosteroid that is used to
treat a variety of inflammatory and allergic disorders. Intravenous doses of
dexamethasone up to 10 times those conventionally used orally are sometimes
employed to treat shock. Substantial systemic absorption of dexamethasone from
topical preparations may occur. Maternal dexamethasone treatment is used to
accelerate fetal lung maturation and prevent respiratory distress syndrome in
pregnancies that are likely to deliver prematurely.
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Magnitude of Teratogenic Risk to
Child Born After Exposure During Gestation: |
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MINIMAL |
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Quality and Quantity of Data on
Which Risk Estimate is Based: |
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FAIR |
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Comments: |
1) FETAL GROWTH RETARDATION MAY BE
ASSOCIATED WITH CHRONIC USE OF DEXAMETHASONE LATE IN PREGNANCY (SEE BELOW). 2) A SMALL RISK OF ORAL CLEFTS MAY BE ASSOCIATED WITH THE
USE OF THERAPEUTIC DOSES OF GLUCOCORTICOIDS DURING THE FIRST TRIMESTER OF
PREGNANCY. |
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Summary of Teratology
Studies:
No association with maternal use of dexamethasone or other
oral corticosteroid preparations was observed in a case control study of 20,830
infants with congenital anomalies (Czeizel & Rockenbauer, 1997). More than
60% of women who took an oral corticosteroid in this study used dexamethasone,
but fewer than 10% of the treatments were in the first trimester.
Dexamethasone treatment of pregnant women has been used to
provide fetal therapy for congenital virilizing adrenal hyperplasia due to a
genetic defect of 21-hydroxylase. Such therapy prevents virilization of most
female fetuses affected with this disease (Lajic et al., 2004; Hughes, 2006;
Nimkarn & New, 2007). No apparent increase in the frequency of congenital
anomalies has been noted among these children, some of whom were treated in the
first trimester of gestation. Two (5%) of 37 Swedish children evaluated at one
to five years of age whose mothers had received dexamethasone treatment during
the first trimester of pregnancy for possible fetal 21-hydroxylase deficiency
had major congenital anomalies in one series (Lajic et al., 1998). Although the
growth and development of these children as a group did not differ from
controls, there were a few instances of growth or developmental delay.
Detailed neuropsychological testing of 26 children in the
Swedish series between seven and 17 years of age showed no difference in
comparison to controls with respect to overall intelligence or most measures of
psychological performance, although poorer performance of the prenatally
exposed children was seen on a subtest of verbal working memory (Hirvikoski et
al., 2007). No significant differences in cognitive or motor development were
found in a comparison of 174 children whose mothers had been treated with
dexamethasone during pregnancy and 313 children whose mothers had not received
such treatment in a study performed through a parental survey (Meyer-Bahlburg
et al., 2004). The average age of the exposed children at the time of study was
5.6 (standard deviation 3.5) years. No significant differences compared to
controls were found in cognitive abilities or behavior problems among 26
six-month to 5.5-year-old children whose mothers were treated with dexamethasone
during pregnancy for possible fetal congenital adrenal hyperplasia in another
series (Trautman et al., 1995). Some differences in measures of temperament
were seen among the exposed children in this study, but this finding requires
confirmation. Growth, psychological development, and school performance of
another series of children who were born after such treatment was said to be
normal on follow-up that extended for up to nine years (Forest & David,
1992). Similarly, no abnormalities were observed on detailed psychometric
testing of 11 two- to 12-year-old children who had been treated with high-dose
dexamethasone in utero for complete heart block (Brucato et al., 2006).
Maternal dexamethasone therapy in the late second or third
trimester of pregnancy accelerates fetal lung maturation and prevents
respiratory distress syndrome in prematurely born infants (
A small but significant decrease in birth weight for
gestational age was found among 961 infants whose mothers were treated with
dexamethasone to promote fetal lung maturation shortly before delivery (Bloom
et al., 2001). No growth, physical, motor, or developmental deficiencies
attributable to such prenatal therapy were observed in a three-year follow-up
study of 200 children delivered to treated women (Collaborative Group on
Antenatal Steroid Therapy, 1984). Maternal dexamethasone treatment shortly
before delivery did not affect neurodevelopmental outcome at 18 to 22 months of
age in 71 infants who had weighed less than 1000 g at birth (LeFlore et al.,
2002).
Several studies suggest that birth weight and head
circumference are reduced and that gastroesophageal reflux and neonatal
mortality are more frequent with repeated courses of maternal corticosteroid
treatment late in pregnancy (Chin et al., 2003; Vidaeff et al., 2003; Baud,
2004; Cavalieri & Cohen, 2006). A follow-up study of 33 infants whose
mothers had received two or more antenatal courses of dexamethasone showed
higher rates of leukomalacia and neurodevelopmental abnormalities at a
corrected age of two years in comparison to infants whose mothers had received
two or more antenatal courses of betamethasone (Spinillo et al., 2004). Lower
than expected head circumference and body mass index, but not height or weight,
were found among 29 six- to ten-year-old children whose mothers had each received
two or more courses of antenatal dexamethasone or betamethasone treatment for
threatened preterm labor in one study (Chen et al., 2008). No adverse effect
was observed on the development of 29 children followed for 11 to 38 months
after birth following intra-amniotic dexamethasone treatment to accelerate
fetal lung maturation (Liu & Zhou, 1985).
Maternal dexamethasone therapy during the second and third
trimester of pregnancy has been used for treatment of fetal heart block
associated with maternal autoimmune disease (Jaeggi et al., 2004). Beneficial
effects appear to occur in some cases, although concerns have been raised about
the safety of this treatment (Costedoat-Chalumeau et al., 2003). Alterations of
the heart rate patterns have been observed in some studies of normal fetuses
whose mothers were treated with dexamethasone for premature labor in the third
trimester of pregnancy (Magee et al., 1997; Mulder et al., 1997; Rotmensch et
al., 1999).
Transient alterations of endocrine function may occur in
infants of women who were treated with dexamethasone or betamethasone late in
pregnancy to induce fetal lung maturation (Ng et al., 1997, 1999; Kallio et
al., 1998; Martin et al., 2005; Koivisto et al., 2007). Concerns have been
raised on the basis of extensive studies in sheep and rats as well as
inferential evidence in humans that prenatal dexamethasone treatment,
especially chronic or recurrent treatment, might predispose to the development
of hypertension or diabetes when an infant reaches adulthood (Ogueh &
Johnson, 2000; Seckl et al., 2000; Seckl, 2001; Baum et al., 2003). No human
data have been reported that directly test this interesting hypothesis.
Scalp aplasia was observed among the offspring of rhesus
monkeys treated in early pregnancy with dexamethasone in doses similar to or
several times greater than those used in humans (Jerome & Hendrickx, 1988).
Cranium bifidum occurred in one of the monkeys with scalp defects. Increased
frequency of cleft palate has been observed among the offspring of mice treated
during pregnancy with 4-10 times the maximal human dose of dexamethasone
(Pinsky & DiGeorge, 1965; Natsume et al., 1986; Senda et al., 2005).
Increased frequencies of palatal, cardiac, and abdominal wall defects were
observed among the offspring of rats treated during pregnancy with
dexamethasone in doses within the human therapeutic range or several times
greater (Vannier & Bremaud, 1985; LaBorde et al., 1992; Chen, 1993; Hansen
et al., 1999).
Fetal weight and head circumference were reduced and
dose-dependent alterations of brain structure and histology were observed among
the offspring of rhesus monkeys treated late in pregnancy with dexamethasone in
doses within or above the human therapeutic range (Novy & Walsh, 1983; Uno
et al., 1990, 1994; Coe & Lubach, 2005). No effect on birth weight but
reduction in postnatal growth, impaired glucose tolerance, and increased blood
pressure were observed in the offspring of African vervets that had been
treated with daily doses of dexamethasone similar to those used in humans (de
Vries et al., 2007). In contrast, increased weight in later infancy was
observed in marmosets born after maternal treatment during pregnancy with
dexamethasone in repeated doses several times those used in humans (Hauser et
al., 2007). Alterations of neurobehavioral and immunological function have also
been observed among juvenile rhesus monkeys or marmosets after maternal
treatment with dexamethasone late in pregnancy in doses similar to or greater
than those used in humans (Coe & Lubach, 2000; Hauser et al., 2007).
Fetal growth retardation, neonatal immune deficiency, and
subsequent alterations of behavior have been reported among the offspring of
mice treated during pregnancy with dexamethasone in doses similar to those
conventionally used in the treatment of asthma and inflammatory diseases in
humans (Rayburn et al., 1997). Fetal and neonatal growth retardation and
alterations of endocrine, immunological, and behavioral function have also been
observed among the offspring of pregnant rats treated with dexamethasone in
doses within the human therapeutic range (Brabham et al., 2000; Smith &
Waddell, 2000; Ortiz et al., 2001, 2003; O'Regan et al., 2004; Burlet et al.,
2005; Emgard et al., 2007). An increased frequency of fetal growth retardation
was observed among the offspring of pregnant rabbits treated dermally with
dexamethasone ointment in a dose that was within the human therapeutic range
but caused maternal toxicity in the rabbits (Esaki et al., 1981). Decreased
brain growth and functional alterations of the hypothalamo-pituitary-adrenal
axis were found in guinea pigs born to mothers that were treated during
pregnancy with dexamethasone in doses 2.5 times greater than the maximum used
in humans (Dean et al., 2001; Liu et al., 2001). Congenital myopathy and fetal
growth retardation were found among the offspring of minipigs treated during
pregnancy with dexamethasone in doses similar to those conventionally used in
the treatment of asthma and inflammatory diseases in humans (Jirmanova &
Lojda, 1985). Decreased brain growth, hypertension, renal abnormalities, and
altered cardiovascular and endocrine function have been observed among the
offspring of pregnant sheep treated with dexamethasone in doses similar to
those used in humans (Dodic et al., 2001, 2002; Wintour et al., 2003; Kutzler
et al., 2004; De Blasio et al., 2007).
PLEASE SEE AGENT
SUMMARY ON PREDNISONE/PREDNISOLONE FOR INFORMATION ON A RELATED AGENT.
Key References: (Each
paper is classified as a review [R], human case report [C], human
epidemiological study [E], human clinical series [S], animal study [A], or
other [O].)
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Bloom SL, Sheffield JS, McIntire DD, Leveno KJ: Antenatal
dexamethasone and decreased birth weight. Obstet Gynecol 97(4):485-490, 2001.
[E]
Brabham T, Phelka A, Zimmer C, Hash A,
Lopez JF, Vazquez DM: Effects of prenatal dexamethasone on spatial learning and
response to stress is influenced by maternal factors. Am J
Physiol Regulatory Integrative Comp Physiol 279(5):R1899-R1909, 2000.
[A]
Brucato A, Astori MG, Cimaz R, Villa P, Li Destri M, Chimini
L, Vaccari R, Muscara M, Motta M, Tincani A, Neri F, Martinelli S: Normal
neuropsychological development in children with congenital complete heart block
who may or may not be exposed to high-dose dexamethasone in utero. Ann Rheum
Dis 65(11):1422-1426, 2006. [S]
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functioning of the hypothalamic-pituitary-adrenal axis of neonates and disturb
some behaviors in juveniles. Neuroscience 133(1):221-230, 2005. [A]
Cavalieri RL, Cohen WR: Antenatal steroid therapy: Have we
undervalued the risks? J Matern Fetal Neonatal Med 19(5):265-269, 2006. [R]
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Chin S-OS, Brodsky NL, Bhandari V:
Antenatal steroid use is associated with increased gastroesophageal reflux in
neonates. Am J Perinatol 20(4):205-213, 2003. [E]
Coe CL, Lubach GR: Developmental consequences of antenatal
dexamethasone treatment in nonhuman primates. Neurosci Biobehav Rev
29(2):227-235, 2005. [R]
Coe CL, Lubach GR: Prenatal influences on neuroimmune set
points in infancy. Ann N Y Acad Sci 917:468-477, 2000. [A]
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1997. [E]
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SG: Prenatal glucocorticoid modifies hypothalamo-pituitary-adrenal regulation
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early pregnancy differentially alters insulin secretion and glucose homeostasis
in adult male sheep offspring. Am J Physiol Endocrinol Metab 293(1):E75-E82, 2007. [A]
de Vries A, Holmes MC, Heijnis A, Seier JV, Heerden J, Louw
J, Wolfe-Coote S, Meaney MJ, Levitt NS, Seckl JR: Prenatal dexamethasone
exposure induces changes in nonhuman primate offspring cardiometabolic and
hypothalamic-pituitary-adrenal axis function. J Clin Invest 117(4):1058-1067,
2007. [A]
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EM, Moritz KM: Programming effects of short prenatal exposure to dexamethasone
in sheep. Hypertension 40(5):729-734, 2002. [A]
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ventricular hypertrophy in adult sheep after prenatal dexamethasone exposure.
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Hauser J, Dettling-Artho A, Pilloud S, Maier C, Knapman A,
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Koivisto M, Peltoniemi OM, Saarela T, Tammela O, Jouppila P,
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[E]
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