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.
Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:
Quality and Quantity of Data on Which Risk Estimate is Based:
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.
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].)
Baud O: Antenatal corticosteroid therapy: benefits and risks. Acta Paediatr 93(Suppl 444):6-10, 2004. [R]
Baum M, Ortiz L, Quan A: Fetal origins of cardiovascular disease. Curr Opin Pediatr 15(2):166-170, 2003. [R]
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]
Burlet G, Fernette B, Blanchard S, Angel E, Tankosic P, Maccari S, Burlet A: Antenatal glucocorticoids blunt the 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]
Chen J: A malformation incidence dose-response model incorporating fetal weight and/or litter size as covariates. Risk Anal 13(3):559-564, 1993. [A]
Chen X-K, Lougheed J, Lawson ML, Gibb W, Walker RC, Wen SW, Walker MC: Effects of repeated courses of antenatal corticosteroids on somatic development in children 6 to 10 years of age. Am J Perinatol 25(1):21-28, 2008. [E]
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]
Collaborative Group on Antenatal Steroid Therapy: Effects of antenatal dexamethasone administration in the infant: Long-term follow-up. J Pediatr 104(2):259-267, 1984. [E]
Costedoat-Chalumeau N, Amoura Z, Le Thi Hong D, Wechsler B, Vauthier D, Ghillani P, Papo T, Fain O, Musset L, Piette J-C: Questions about dexamethasone use for the prevention of anti-SSA related congenital heart block. Ann Rheum Dis 62(10):1010-1012, 2003. [S]
Czeizel AE, Rockenbauer M: Population-based case-control study of teratogenic potential of corticosteroids. Teratology 56(5):335-340, 1997. [E]
Dean F, Yu C, Lingas RI, Matthews SG: Prenatal glucocorticoid modifies hypothalamo-pituitary-adrenal regulation in prepubertal guinea pigs. Neuroendocrinology 73(3):194-202, 2001. [A]
De Blasio MJ, Dodic M, Jefferies AJ, Moritz KM, Wintour EM, Owens JA: Maternal exposure to dexamethasone or cortisol in 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]
Dodic M, Abouantoun T, O'Connor A, Wintour EM, Moritz KM: Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension 40(5):729-734, 2002. [A]
Dodic M, Samuel C, Moritz K, Wintour EM, Morgan J, Grigg L, Wong J: Impaired cardiac functional reserve and left ventricular hypertrophy in adult sheep after prenatal dexamethasone exposure. Circ Res 89(7):623-629, 2001. [A]
Emgard M, Paradisi M, Pirondi S, Fernandez M, Giardino L, Calza L: Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons. Neurobiol Aging 28(1):112-121, 2007. [A]
Esaki K, Shikata Y, Yanagita T: [Effects of dermal administration of dexamethasone 17-valerate in rabbit fetuses.] Jitchuken Zenrinsho Kenkyuho 7:245-256, 1981. [A]
Forest MG, David M: Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A 10 year experience. Indian J Pediatr 59(4):515-522, 1992. [S]
Hansen DK, LaBorde JB,
Hauser J, Dettling-Artho A, Pilloud S, Maier C, Knapman A, Feldon J, Pryce CR: Effects of prenatal dexamethasone treatment on postnatal physical, endocrine, and social development in the common marmoset monkey. Endocrinology 148(4):1813-1822, 2007. [A]
Hirvikoski T, Nordenstrom A, Lindholm T, Lindblad F, Ritzen EM, Wedell A, Lajic S: Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab 92(2):542-548, 2007. [E]
Hughes I: Prenatal treatment of congenital adrenal hyperplasia. Do we have enough evidence? Treat Endocrinol 5(1):1-6, 2006. [O]
Jaeggi ET, Fouron J-C, Silverman ED, Ryan G, Smallhorn J, Hornberger LK: Transplacental fetal treatment improves the outcome of prenatally diagnosed complete atrioventricular block without structural heart disease. Circulation 110(12):1542-1548, 2004. [E]
Jerome CP, Hendrickx AG: Comparative teratogenicity of triamcinolone acetonide and dexamethasone in the rhesus monkey (Macaca mulatta). J Med Primatol 17(4):195-203, 1988. [A]
Jirmanova I, Lojda L: Dexamethasone applied to pregnant minisows induces splayleg in minipiglets. Zentralbl Veterinarmed A 32(6):445-458, 1985. [A]
Kallio J, Karlsson R, Toppari J, Helminen T, Scheinin M, Kero P: Antenatal dexamethasone treatment decreases plasma catecholamine levels in preterm infants. Pediatr Res 43(6):801-807, 1998. [E]
Koivisto M, Peltoniemi OM, Saarela T, Tammela O, Jouppila P, Hallman M: Blood glucose level in preterm infants after antenatal exposure to glucocorticoid. Acta Paediatr 96(5):664-668, 2007. [E]
Kutzler MA, Ruane EK, Coksaygan T, Vincent SE, Nathanielsz PW: Effects of three courses of maternally administered dexamethasone at 0.7, 0.75, and 0.8 of gestation on prenatal and postnatal growth in sheep. Pediatrics 113(2):313-319, 2004. [A]
LaBorde JB, Hansen DK, Young JF, Sheehan DM, Holson RR: Prenatal dexamethasone exposure in rats: Effects of dose, age at exposure, and drug-induced hypophagia on malformations and fetal organ weights. Fundam Appl Toxicol 19(4):545-554, 1992. [A]
Lajic S, Nordenstrom A, Ritzen EM, Wedell A: Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 151(Suppl 3):U63-U69, 2004. [E]
Lajic S, Wedell A, Bui T-H, Ritzen EM, Holst M: Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 83(11):3872-3880, 1998. [E]
Liu L, Li A, Matthews SG: Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. Am J Physiol Endocrinol Metab 280(5):E729-E739, 2001. [A]
Liu D-L, Zhou Z-L: Enhancement of fetal lung maturity by intra-amniotic instillation of dexamethasone. Chin Med J 98(12):915-918, 1985. [E]
Magee LA, Dawes GS, Moulden M, Redman CWG: A randomised controlled comparison of betamethasone with dexamethasone: Effects on the antenatal fetal heart rate. Br J Obstet Gynaecol 104(11):1233-1238, 1997. [E]
Martin CR, Van Marter LJ, Allred EN, Leviton A: Antenatal glucocorticoids increase early total thyroxine levels in premature infants. Biol Neonate 87(4):273-280, 2005. [E]
Meyer-Bahlburg HFL, Dolezal C, Baker SW, Carlson AD, Obeid JS, New MI: Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. J Clin Endocrinol Metab 89(2):610-614, 2004. [E]
Mulder EJH, Derks JB, Visser GHA: Antenatal corticosteroid therapy and fetal behaviour: A randomised study of the effects of betamethasone and dexamethasone. Br J Obstet Gynaecol 104(11):1239-1247, 1997. [E]
Natsume N, Narukawa T, Kawai T: Teratogenesis of dexamethasone and preventive effect of vitamin B12. Int J Oral Maxillofac Surg 15(6):752-755, 1986. [A]
Ng PC, Wong GWK, Lam CWK, Lee CH, Fok TF, Wong MY, Ma KC: Effects of multiple courses of antenatal corticosteroids on pituitary-adrenal function in preterm infants. Arch Dis Child Fetal Neonatal Ed 80(3):F213-F216, 1999. [E]
Ng PC, Wong GWK, Lam CWK, Lee CH, Wong MY, Fok TF, Wong W,
Nimkarn S, New MI: Prenatal diagnosis and treatment of congenital adrenal hyperplasia. Horm Res 67(2):53-60, 2007. [R]
Novy MJ, Walsh SW: Dexamethasone and estradiol treatment in pregnant rhesus macaques: Effects on gestational length, maternal plasma hormones, and fetal growth. Am J Obstet Gynecol 145(8):920-931, 1983. [A]
Ogueh O, Johnson MR: The metabolic effect of antenatal corticosteroid therapy. Hum Reprod Update 6(2):169-176, 2000. [R] & [E]
O'Regan D, Kenyon CJ, Seckl JR, Holmes MC: Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. Am J Physiol Endocrinol Metab 287(5):E863-E870, 2004. [A]
Ortiz LA, Quan A, Weinberg A, Baum M: Effect of prenatal dexamethasone on rat renal development. Kidney Int 59(5):1663-1669, 2001. [A]
Ortiz LA, Quan A, Zarzar F, Weinberg A, Baum M: Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 41(2):328-334, 2003. [A]
Pinsky L, DiGeorge AM: Cleft palate in the mouse: A teratogenic index of glucocorticoid potency. Science 147:402-403, 1965. [A]
Rayburn WF, Christensen HD, Gonzalez CL: A placebo-controlled comparison between betamethasone and dexamethasone for fetal maturation: Differences in neurobehavioral development of mice offspring. Am J Obstet Gynecol 176(4):842-851, 1997. [A]
Roberts D, Dalziel S: Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 3: CD004454, 2006. [E]
Rotmensch S, Liberati M, Vishne TH, Celentano C, Ben-Rafael Z, Bellati U: The effect of betamethasone and dexamethasone on fetal heart rate patterns and biophysical activities. A prospective randomized trial. Acta Obstet Gynecol Scand 78(6):493-500, 1999. [E]
Seckl JR: Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol Cell Endocrinol 185(1-2):61-71, 2001. [R]
Seckl JR, Cleasby M, Nyirenda MJ: Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 57(4):1412-1417, 2000. [O]
Senda T, Natsume N, Kuno J, Toyoda T, Shimozato K: Rate of occurrence of dexamethasone-induced cleft palate affected by uterine environment in the mouse. Plast Reconstr Surg 115(4):1208-1210, 2005. [A]
Smith JT, Waddell BJ: Increased fetal glucocorticoid exposure delays puberty onset in postnatal life. Endocrinology 141(7):2422-2428, 2000. [A]
Spinillo A, Viazzo F, Colleoni R, Chiara A, Maria Cerbo R, Fazzi E: Two-year infant neurodevelopmental outcome after single or multiple antenatal courses of corticosteroids to prevent complications of prematurity. Am J Obstet Gynecol 191(1):217-224, 2004. [E]
Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI: Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: Results of a pilot study. Psychoneuroendocrinology 20(4):439-449, 1995. [E]
Uno H, Eisele S,
Uno H, Lohmiller L, Thieme C, Kemnitz JW, Engle MJ, Roecker EB, Farrell PM: Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Dev Brain Res 53(2):157-167, 1990. [A]
Vannier B, Bremaud R: Induction of heart defects in the rat foetus with dexamethasone. Teratology 32(2):35A, 1985. [A]
Wintour EM, Moritz KM, Johnson K, Ricardo S, Samuel CS, Dodic M: Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol 549(3):929-935, 2003. [A]