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TRIAMCINOLONE

Fetal Risk Summary

Triamcinolone is a synthetic fluorinated corticosteroid that can be administered, depending on the preparation selected, orally, parenterally, topically, or by oral inhalation. In animal models of inflammation, triamcinolone is approximately 1–2 times as potent as prednisone, whereas triamcinolone acetonide is about 8 times more potent (1). Oral inhalation of usual therapeutic doses of the latter agent do not appear to suppress the hypothalamic-pituitary-adrenal axis (2).

Triamcinolone is teratogenic in animals. Cleft palate was induced in fetal mice and rats exposed in utero to triamcinolone, triamcinolone acetonide, or triamcinolone diacetate (3,4 and 5). In one study with mice, high dietary fat intake (48% compared with a low-fat diet of 5.6%) increased the frequency and severity of cleft palate (5). Intramuscular administration of nonlethal maternal doses (0.125–0.5 mg/kg/day) of triamcinolone acetonide in pregnant rats at various gestational ages produced fetal growth retardation at all doses tested (6). Higher doses were associated with resorption, cleft palate, umbilical hernias, undescended testes, and reduced ossification (6). A second report by these latter investigators compared the teratogenic potency, as measured by the induction of cleft palate, of triamcinolone, triamcinolone acetonide, and cortisol in rats (7). Triamcinolone acetonide was 59 times more potent than triamcinolone, which, in turn, was more potent than cortisol. Other anomalies observed with triamcinolone acetonide were umbilical hernias, resorption, and fetal death. All three agents produced fetal growth retardation.

Morphologically abnormal lungs and increased epithelial maturation were found in fetal rat whole-organ lung cultures exposed to triamcinolone acetonide (8). Similarly, accelerated fetal lung maturation was observed following administration of IM triamcinolone acetonide to pregnant rhesus macaques at various stages of gestation (9). However, treatment earlier in gestation produced growth retardation of some of the lung septa, as well as decreased body weight and length (9).

A series of studies described the teratogenic effects of single and multiple doses of IM triamcinolone acetonide administered early in gestation to nonhuman primates (bonnet monkeys, rhesus monkeys, and baboons) at doses ranging from approximately equivalent to the human dose up to 300 times the human dose (10,11,12 and 13). Resorption, intrauterine death, orocraniofacial anomalies, and defects of the thorax, hindlimbs, thymus, adrenal, and kidney were observed. The most common malformations involved the central nervous system and cranium in all three species (11); growth retardation was also common in all species (10).

Published human pregnancy experience with triamcinolone is limited to 16 cases. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 56 of whom were exposed during the 1st trimester to a category of miscellaneous corticosteroids (14). Included in this group were 8 triamcinolone-exposed mother-child pairs. Two (3.6%; relative risk 0.47) newborns with malformations were observed in the total group, suggesting a lack of any relationship to large categories of major or minor malformations or to individual defects.

A 1966 Reference described a woman with benign adrenogenital syndrome who took 4–8 mg of triamcinolone orally throughout gestation (15). She delivered a normal 2.61-kg male infant at 38 weeks without evidence of hypoadrenalism. A 1975 report included 5 patients treated with triamcinolone acetonide, presumably by oral inhalation, among 70 women with asthma who were treated with various corticosteroids throughout gestation (16). No adverse fetal outcomes were observed in the five triamcinolone-exposed cases, although one of the mothers delivered prematurely. None of the 70 newborns had evidence of adrenal insufficiency.

Symmetrical growth retardation was observed in a 700-g, small-for-gestational age newborn delivered via cesarean section at 31 weeks' gestation because of fetal distress, diminished amniotic fluid, and lack of growth (17). The Dubowitz evaluation was compatible with the menstrual dates. The normotensive, nonsmoking mother had applied 0.05% triamcinolone acetonide cream to her legs, abdomen, and extremities for atopic dermatitis from 12 to 29 weeks' gestation. The authors estimated her daily dose to be approximately 40 mg, but she had no signs or symptoms of adrenal insufficiency. The newborn was breathing room air within 12 hours without evidence of respiratory distress. Although not discussed, the apparent fetal lung maturity in a 31-week fetus may have been the result of chronic corticosteroid exposure. At 14 days of age, necrotizing enterocolitis occurred and, following multiple surgeries, the infant was alive at 10 months of age on total parenteral nutrition. In an addendum to their report, the authors noted that the mother had had a second pregnancy, this time without the use of triamcinolone, and delivered a 1660-g (10th percentile for gestational age) male infant at 34 weeks' gestation. The authors attributed the growth retardation in the first infant to triamcinolone because no other cause was discovered. The result of the second pregnancy, however, probably indicates that other factors were involved in addition to any effect of the corticosteroid.

Four large epidemiologic studies have associated the use of corticosteroids during the 1st trimester with orofacial clefts. The specific corticosteroid was not identified in three of these studies (see Hydrocortisone for details), but in a 1999 study described below, the corticosteroids were listed.

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) (18). 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%) (18). 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 infants with ICLP and three of infants with 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 1.1–17.2), whereas the odds ratio for ICP and corticosteroid use was 5.3 (95% confidence interval 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 (18).

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

Breast Feeding Summary

No reports describing the use of triamcinolone during lactation have been located. The molecular weight (about 394) is low enough, however, that excretion into breast milk should be expected. Small amounts of other corticosteroids (see also Hydrocortisone and Prednisone) are excreted into milk and do not appear to present a risk to a nursing infant. Similar excretion probably occurs following inhaled triamcinolone. At least one source states that inhaled corticosteroids used for asthma are not contraindicated during breast feeding (19). No data are available to assess the potential risk to a nursing infant following systemic use of triamcinolone in a breast-feeding woman.

References

1. Product information. Azmacort. Rhône-Poulenc Rorer Pharmaceuticals, Inc., 1994.
2. American Hospital Formulary Service. Drug Information 1997. Bethesda, MD: American Society of Health-System Pharmacists, 1997:2368–70.
3. Walker BE. Cleft palate produced in mice by human-equivalent dosage with triamcinolone. Science 1965;149:862–3.
4. Walker BE. Induction of cleft palate in rats with antiinflammatory drugs. Teratology 1971;4:39–42.
5. Zhou M, Walker BE. Potentiation of triamcinolone-induced cleft palate in mice by maternal high dietary fat. Teratology 1993;48:53–7.
6. Rowland JM, Hendrickx AG. Teratogenicity of triamcinolone acetonide in rats. Teratology 1983;27:13–8.
7. Rowland JM, Hendrickx AG. Comparative teratogenicity of triamcinolone acetonide, triamcinolone, and cortisol in the rat. Teratogenesis Carcinog Mutagen 1983;3:313–9.
8. Massoud EAS, Sekhon HS, Rotschild A, Thurlbeck WM. The in vitro effect of triamcinolone acetonide on branching morphogenesis in the fetal rat lung. Pediatr Pulmonol 1992;14:28–36.
9. Bunton TE, Plopper CG. Triamcinolone-induced structural alterations in the development of the lung of the fetal rhesus macaque. Am J Obstet Gynecol 1984;148:203–15.
10. Hendrickx AG, Sawyer RH, Terrell TG, Osburn BI, Hendrickson RV, Steffek AJ. Teratogenic effects of triamcinolone on the skeletal and lymphoid systems in nonhuman primates. Fed Proc 1975;34:1661–5.
11. Hendrickx AG, Pellegrini M, Tarara R, Parker R, Silverman S, Steffek AJ. Craniofacial and central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: I. General teratogenicity. Teratology 1980;22:103–14.
12. Parker RM, Hendrickx AG. Craniofacial and central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: II. Craniofacial pathogenesis. Teratology 1983;28:35–44.
13. Tarara RP, Cordy DR, Hendrickx AG. Central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: pathology. Teratology 1989;39:75–84.
14. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:388–400.
15. Rolf BB. Corticosteroids and pregnancy. Am J Obstet Gynecol 1966;95:339–44.
16. Schatz M, Patterson R, Zeitz S, O'Rourke J, Melam H. Corticosteroid therapy for the pregnant asthmatic patient. JAMA 1975;233:804–7.
17. Katz VL, Thorp JM Jr, Bowes WA Jr. Severe symmetric intrauterine growth retardation associated with the topical use of triamcinolone. Am J Obstet Gynecol 1990;162:396–7.
18. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242–4.
19. Report of the Working Group on Asthma and Pregnancy. Management of asthma during pregnancy. U.S. Department of Health and Human Services, NIH Publication No. 93–3279, 1993:19.
    
    

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