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DEXAMETHASONE

Fetal Risk Summary

Although most sources have not linked the use of dexamethasone with congenital defects, four large epidemiologic studies have found positive associations between systemic corticosteroids and nonsyndromic orofacial clefts. Specific corticosteroids were not identified in three of these studies (see Hydrocortisone for details), but dexamethasone and other agents were listed in a 1999 study discussed below.

In a case-control study, the California Birth Defects Monitoring Program evaluated the association between selected congenital anomalies and the use of corticosteroids 1 month before to 3 months after conception (periconceptional period) (1). Case infants or fetal deaths diagnosed with orofacial clefts, conotruncal defects, neural tubal defects (NTD), and limb anomalies were identified from a total of 552,601 births that occurred from 1987 through the end of 1989. Controls, without birth defects, were selected from the same database. Following exclusion of known genetic syndromes, mothers of case and control infants were interviewed by telephone, an average of 3.7 years (cases) or 3.8 years (controls) after delivery, to determine various exposures during the periconceptional period. The number of interviews completed were orofacial cleft case mothers (N=662, 85% of eligible), conotruncal case mothers (N=207, 87%), NTD case mothers (N=265, 84%), limb anomaly case mothers (N=165, 82%), and control mothers (N=734, 78%) (1). Orofacial clefts were classified into four phenotypic groups: isolated cleft lip with or without cleft palate (ICLP, N=348), isolated cleft palate (ICP, N=141), multiple cleft lip with or without cleft palate (MCLP, N=99), and multiple cleft palate (MCP, N=74). A total of 13 mothers reported using corticosteroids during the periconceptional period for a wide variety of indications. Six case mothers of ICLP and 3 of ICP used corticosteroids (unspecified corticosteroid N=1, prednisone N=2, cortisone N=3, triamcinolone acetonide N=1, dexamethasone N=1, and cortisone plus prednisone N=1). One case mother of an infant with NTD used cortisone and an injectable unspecified corticosteroid, and three controls used corticosteroids (hydrocortisone N=1 and prednisone N=2). The odds ratio for corticosteroid use and ICLP was 4.3 (95% confidence interval [CI] 1.1–17.2), whereas the odds ratio for ICP and corticosteroid use was 5.3 (95% CI 1.1–26.5). No increased risks were observed for the other anomaly groups. Commenting on their results, the investigators thought that recall bias was unlikely because they did not observe increased risks for other malformations, and it was also unlikely that the mothers would have known of the suspected association between corticosteroids and orofacial clefts (1).

Maternal free estriol and cortisol are significantly depressed after dexamethasone therapy, but the effects of these changes on the fetus have not been studied (2,3 and 4).

Dexamethasone has been used in patients with premature labor at about 26–34 weeks' gestation to stimulate fetal lung maturation (5,6,7,8,9,10,11,12,13,14 and 15). Although this therapy is supported by many clinicians, its use is still controversial since the beneficial effects of steroids are greatest in singleton pregnancies with female fetuses (16,17,18 and 19). These benefits are: Reduction in incidence of respiratory distress syndrome (RDS) Decreased severity of RDS if it occurs Decreased incidence of and mortality from intracranial hemorrhage Increased survival of premature infants Toxicity in the fetus and newborn following the use of dexamethasone is rare.

In studies of women with premature rupture of the membranes (PROM), administration of corticosteroids does not always reduce the frequency of RDS or perinatal mortality (20,21 and 22). In addition, an increased risk of maternal infection has been observed in patients with PROM treated with corticosteroids (21,22). A recent report, however, found no difference in the incidence of maternal complications between treated and nontreated patients (23).

Dexamethasone crosses the placenta to the fetus (24,25). The drug is partially metabolized (54%) by the perfused placenta to its inactive 11-ketosteroid derivative, more so than betamethasone, but the difference is not statistically significant (25).

Leukocytosis has been observed in infants exposed antenatally to dexamethasone (26,27). The white blood cell counts returned to normal in about a week.

The use of corticosteroids, including dexamethasone, for the treatment of asthma during pregnancy has not been related to a significantly increased risk of maternal or fetal complications (28). A slight increase in the number of premature births was found, but it could not be determined whether this was an effect of the corticosteroids. An earlier study also recorded a shortening of gestation with chronic corticosteroid use (29).

In Rh-sensitized women, the use of dexamethasone may have prevented intrauterine fetal deterioration and the need for fetal transfusion (30). Five women, in the 2nd and 3rd trimesters, were treated with 24 mg of the steroid weekly for 2–7 weeks resulting, in each case, in a live newborn.

Dexamethasone, 4 mg/day for 15 days, was administered to a woman late in the 3rd trimester for the treatment of autoimmune thrombocytopenic purpura (31). Therapy was given in an unsuccessful attempt to prevent fetal/neonatal thrombocytopenia due to the placental transfer of antiplatelet antibody. Platelet counts in the newborn were 38,000–49,000/mm3, but the infant made an uneventful recovery.

The use of dexamethasone for the pharmacologic suppression of the fetal adrenal gland has been described in two women with 21-hydroxylase deficiency (32,33). This deficiency results in the overproduction of adrenal androgens and the virilization of female fetuses. Dexamethasone, in divided doses of 1 mg/day, was administered from early in the 1st trimester (5th week and 10th week) to term. Normal female infants resulted from both pregnancies.

Although human studies have usually shown a benefit, the use of corticosteroids in animals has been associated with several toxic effects (34,35): Reduced fetal head circumference Reduced fetal adrenal weight Increased fetal liver weight Reduced fetal thymus weight Reduced placental weight Fortunately, none of these effects has been observed in human investigations. Long-term follow-up evaluations of children exposed in utero to dexamethasone have shown no adverse effects from this exposure (36,37).

[*Risk Factor D if used in 1st trimester.]

Breast Feeding Summary

No reports describing the use of dexamethasone during lactation have been located. The molecular weight (about 516) is low enough for passage into breast milk. Moreover, trace amounts of other corticosteroids are excreted into milk (e.g., see Hydrocortisone and Prednisone), and the excretion of dexamethasone into milk should be expected.

References

1. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242–4.
2. Reck G, Nowostawski, Bredwoldt M. Plasma levels of free estriol and cortisol under ACTH and dexamethasone during late pregnancy. Acta Endocrinol 1977;84:86–7.
3. Kauppilla A. ACTH levels in maternal, fetal and neonatal plasma after short term prenatal dexamethasone therapy. Br J Obstet Gynaecol 1977;84:128–34.
4. Warren JC, Cheatum SG. Maternal urinary estrogen excretion: effect of adrenal suppression. J Clin Endocrinol 1967;27:436–8.
5. Caspi I, Schreyer P, Weinraub Z, Reif R, Levi I, Mundel G. Changes in amniotic fluid lecithin-sphingomyelin ratio following maternal dexamethasone administration. Am J Obstet Gynecol 1975;122:327–31.
6. Spellacy WN, Buhi WC, Riggall FC, Holsinger KL. Human amniotic fluid lecithin/sphingomyelin ratio changes with estrogen or glucocorticoid treatment. Am J Obstet Gynecol 1973;115:216–8.
7. Caspi E, Schreyer P, Weinraub Z, Reif R, Levi I, Mundel G. Prevention of the respiratory distress syndrome in premature infants by antepartum glucocorticoid therapy. Br J Obstet Gynaecol 1976;83:187–93.
8. Ballard RA, Ballard PL. Use of prenatal glucocorticoid therapy to prevent respiratory distress syndrome. Am J Dis Child 1976;130:982–7.
9. Thornfeldt RE, Franklin RW, Pickering NA, Thornfeldt CR, Amell G. The effect of glucocorticoids on the maturation of premature lung membranes: preventing the respiratory distress syndrome by glucocorticoids. Am J Obstet Gynecol 1978;131:143–8.
10. Ballard PL, Ballard RA. Corticosteroids and respiratory distress syndrome: status 1979. Pediatrics 1979;63:163–5.
11. Taeusch HW Jr, Frigoletto F, Kitzmiller J, Avery ME, Hehre A, Fromm B, Lawson E, Neff RK. Risk of respiratory distress syndrome after prenatal dexamethasone treatment. Pediatrics 1979;63:64–72.
12. Caspi E, Schreyer P, Weinraub Z, Lifshitz Y, Goldberg M. Dexamethasone for prevention of respiratory distress syndrome: multiple perinatal factors. Obstet Gynecol 1981;57:41–7.
13. Bishop EH. Acceleration of fetal pulmonary maturity. Obstet Gynecol 1981;58(Suppl):48S–51S.
14. Farrell PM, Engle MJ, Zachman RD, Curet LB, Morrison JC, Rao AV, Poole WK. Amniotic fluid phospholipids after maternal administration of dexamethasone. Am J Obstet Gynecol 1983;145:484–90.
15. Ruvinsky ED, Douvas SG, Roberts WE, Martin JN Jr, Palmer SM, Rhodes PG, Morrison JC. Maternal administration of dexamethasone in severe pregnancy-induced hypertension. Am J Obstet Gynecol 1984;149:722–6.
16. Avery ME. The argument for prenatal administration of dexamethasone to prevent respiratory distress syndrome. J Pediatr 1984;104:240.
17. Sepkowitz S. Prenatal corticosteroid therapy to prevent respiratory distress syndrome. J Pediatr 1984;105:338–9.
18. Avery ME. Prenatal corticosteroid therapy to prevent respiratory distress syndrome (reply). J Pediatr 1984;105:339.
19. Levy DL. Maternal administration of dexamethasone to prevent RDS. J Pediatr 1984;105:339.
20. Eggers TR, Doyle LW, Pepperell RJ. Premature rupture of the membranes. Med J Aust 1979;1:209–13.
21. Garite TJ, Freeman RK, Linzey EM, Braly PS, Dorchester WL. Prospective randomized study of corticosteroids in the management of premature rupture of the membranes and the premature gestation. Am J Obstet Gynecol 1981;141:508–15.
22. Garite TJ. Premature rupture of the membranes: the enigma of the obstetrician. Am J Obstet Gynecol 1985;151:1001–5.
23. Curet LB, Morrison JC, Rao AV. Antenatal therapy with corticosteroids and postpartum complications. Am J Obstet Gynecol 1985;152:83–4.
24. Osathanondh R, Tulchinsky D, Kamali H, Fencl MdeM, Taeusch HW Jr. Dexamethasone levels in treated pregnant women and newborn infants. J Pediatr 1977;90:617–20.
25. Levitz M, Jansen V, Dancis J. The transfer and metabolism of corticosteroids in the perfused human placenta. Am J Obstet Gynecol 1978;132:363–6.
26. Otero L, Conlon C, Reynolds P, Duval-Arnould B, Golden SM. Neonatal leukocytosis associated with prenatal administration of dexamethasone. Pediatrics 1981;68:778–80.
27. Anday EK, Harris MC. Leukemoid reaction associated with antenatal dexamethasone administration. J Pediatr 1982;101:614–6.
28. Schatz M, Patterson R, Zeitz S, O'Rourke J, Melam H. Corticosteroid therapy for the pregnant asthmatic patient. JAMA 1975;233:804–7.
29. Jenssen H, Wright PB. The effect of dexamethasone therapy in prolonged pregnancy. Acta Obstet Gynecol Scand 1977;56:467–73.
30. Navot D, Rozen E, Sadovsky E. Effect of dexamethasone on amniotic fluid absorbance in Rh-sensitized pregnancy. Br J Obstet Gynaecol 1982;89:456–8.
31. Yin CS, Scott JR. Unsuccessful treatment of fetal immunologic thrombocytopenia with dexamethasone. Am J Obstet Gynecol 1985;152:316–7.
32. David M, Forest MG. Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 1984;105:799–803.
33. Evans MI, Chrousos GP, Mann DW, Larsen JW Jr, Green I, McCluskey J, Loriaux L, Fletcher JC, Koons G, Overpeck J, Schulman JD. Pharmacologic suppression of the fetal adrenal gland in utero. JAMA 1985;253:1015–20.
34. Taeusch HW Jr. Glucocorticoid prophylaxis for respiratory distress syndrome: a review of potential toxicity. J Pediatr 1975;87:617–23.
35. Johnson JWC, Mitzner W, London WT, Palmer AE, Scott R. Betamethasone and the rhesus fetus: multisystemic effects. Am J Obstet Gynecol 1979;133:677–84.
36. Wong YC, Beardsmore CS, Silverman M. Antenatal dexamethasone and subsequent lung growth. Arch Dis Child 1982;57:536–8.
37. Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: long-term follow-up. J Pediatr 1984;104:259–67.
    
    

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