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PREDNISONE

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Fetal Risk Summary

Prednisone is metabolized to prednisolone. There are a number of studies in which pregnant patients received either prednisone or prednisolone (see also various antineoplastic agents for additional References) (1,2,3,4,5,6,7,8,9,10,11,12,13 and 14).

Although most reports describing the use of prednisone or prednisolone during gestation have not observed abnormal outcomes, four large epidemiologic studies have associated the use of corticosteroids in the 1st trimester with nonsyndromic orofacial clefts. Specific agents were not identified in three of these studies (see Hydrocortisone for details), but in one 1999 study, discussed 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) (15). Case infants or fetal deaths diagnosed with orofacial clefts, conotruncal defects, neural tubal defects (NTDs), 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 data base. 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%) (15). 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 [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 (15).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 143, 236, and 222 newborns had been exposed to prednisolone, prednisone, and methylprednisolone, respectively, during the 1st trimester (F. Rosa, personal communication, FDA, 1993). The number of birth defects, the number expected, and the percent for each drug were 11/6 (7.7%), 11/10 (4.7%), and 14/9 (6.3%), respectively. Specific details were available for six defect categories (observed/expected): cardiovascular defects (2/1, 2/2, 3/2), oral clefts (0/0, 0/0, 0/0), spina bifida (0/0, 0/0, 0/0), polydactyly (0/0, 0/1, 0/1), limb reduction defects (0/0, 0/0, 1/0), and hypospadias (1/0, 0/1, 1/1), respectively. These data do not support an association between the drugs and congenital defects, except for a possible association between prednisolone and the total number of defects. In the latter case, other factors, such as the mother's disease, concurrent drug use, and chance may be involved.

Immunosuppression was observed in a newborn exposed to high doses of prednisone with azathioprine throughout gestation (16). The newborn had lymphopenia, decreased survival of lymphocytes in culture, absence of IgM, and reduced levels of IgG. Recovery occurred at 15 weeks of age. However, these effects were not observed in a larger group of similarly exposed newborns (17). A 1968 study reported an increase in the incidence of stillbirths following prednisone therapy during pregnancy (7). Increased fetal mortality has not been confirmed by other investigators.

An infant exposed to prednisone throughout pregnancy was born with congenital cataracts (1). The eye defect was consistent with reports of subcapsular cataracts observed in adults receiving corticosteroids. The relationship in this case between the cataracts and prednisone is unknown, but other reports have also described cataracts after corticosteroid use during gestation (see Hydrocortisone).

In a 1970 case report, a female infant with multiple deformities was described (18). Her father had been treated several years before conception with prednisone, azathioprine, and radiation for a kidney transplant. The authors speculated that the child's defects may have been related to the father's immunosuppressive therapy. A relationship to prednisone seems remote because previous studies have shown that the drug has no effect on chromosome number or morphology (19). High, prolonged doses of prednisolone (30 mg/day for at least 4 weeks) may damage spermatogenesis (20). Recovery may require 6 months after the drug is stopped.

Prednisone has been used successfully to prevent neonatal respiratory distress syndrome when premature delivery occurs between 28 and 36 weeks of gestation (21). Therapy between 16 and 25 weeks of gestation had no effect on lecithin:sphingomyelin ratios (22).

In summary, prednisone and prednisolone apparently pose a small risk to the developing fetus. One of these risks appears to be orofacial clefts. Although the available evidence supports their use to control various maternal diseases, the mother should be informed of this risk so that she can actively participate in the decision on whether to use these agents during her pregnancy.

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

Breast Feeding Summary

Trace amounts of prednisone and prednisolone have been measured in breast milk (23,24,25 and 26). Following a 10-mg oral dose of prednisone, milk concentrations of prednisone and prednisolone at 2 hours were 26.7 and 1.6 ng/mL, respectively (23). The authors estimated the infant would ingest approximately 28.3 µg in 1000 mL of milk. In a second study using radioactive-labeled prednisolone in seven patients, a mean of 0.14% of a 5-mg oral dose was recovered per liter of milk during 48–61 hours (24).

In six lactating women, prednisolone doses of 10–80 mg/day resulted in milk concentrations ranging from 5% to 25% of maternal serum levels (25). The milk:plasma ratio increased with increasing serum concentrations. For maternal doses of 20 mg once or twice daily, the authors concluded that the nursing infant would be exposed to minimal amounts of steroid. At higher doses, they recommended waiting at least 4 hours after a dose before nursing was performed. However, even at 80 mg/day, the nursing infant would ingest <0.1% of the dose, which corresponds to <10% of the infant's endogenous cortisol production (25).

A 1993 report described the pharmacokinetics of prednisolone in milk (26). Following a 50-mg intravenous dose, an average of 0.025% (range 0.010%–0.049%) was recovered from the milk. The data suggested a rapid, bidirectional transfer of unbound prednisolone between the milk and serum (26). The investigators concluded that the measured milk concentrations of the steroid did not pose a clinically significant risk to a nursing infant.

Although nursing infants were not involved in the above studies, it is doubtful whether the amounts measured are clinically significant. The American Academy of Pediatrics considers prednisone to be compatible with breast feeding (27).

References

1. Kraus AM. Congenital cataract and maternal steroid injection. J Pediatr Ophthalmol 1975;12:107–8.
2. Durie BGM, Giles HR. Successful treatment of acute leukemia during pregnancy: Combination therapy in the third trimester. Arch Intern Med 1977;137:90–1.
3. Nolan GH, Sweet RL, Laros RK, Roure CA. Renal cadaver transplantation followed by successful pregnancies. Obstet Gynecol 1974;43:732–9.
4. Grossman JH III, Littner MR. Severe sarcoidosis in pregnancy. Obstet Gynecol 1977;50(Suppl):81s–4s.
5. Cutting HO, Collier TM. Acute lymphocytic leukemia during pregnancy: Report of a case. Obstet Gynecol 1964;24:941–5.
6. Hanson GC, Ghosh S. Systemic lupus erythematosus and pregnancy. Br Med J 1965;2:1227–8.
7. Warrell DW, Taylor R. Outcome for the foetus of mothers receiving prednisolone during pregnancy. Lancet 1968;1:117–8.
8. Walsh SD, Clark FR. Pregnancy in patients on long-term corticosteroid therapy. Scott Med J 1967;12:302–6.
9. Zulman JI, Talal N, Hoffman GS, Epstein WV. Problems associated with the management of pregnancies in patients with systemic lupus erythematosus. J Rheumatol 1980;7:37–49.
10. Hartikainen-Sorri AL, Kaila J. Systemic lupus erythematosus and habitual abortion: Case report. Br J Obstet Gynaecol 1980;87:729–31.
11. Minchinton RM, Dodd NJ, O'Brien H, Amess JAL, Waters AH. Autoimmune thrombocytopenia in pregnancy. Br J Haematol 1980;44:451–9.
12. Tozman ECS, Urowitz MB, Gladman DD. Systemic lupus erythematosus and pregnancy. J Rheumatol 1980;7:624–32.
13. Karpatkin M, Porges RF, Karpatkin S. Platelet counts in infants of women with autoimmune thrombocytopenia: Effect of steroid administration to the mother. N Engl J Med 1981;305:936–9.
14. Pratt WR. Allergic diseases in pregnancy and breast feeding. Ann Allergy 1981;47:355–60.
15. Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86:242–4.
16. Cote CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr 1974;85:324–8.
17. Cederqvist LL, Merkatz IR, Litwin SD. Fetal immunoglobulin synthesis following maternal immunosuppression. Am J Obstet Gynecol 1977;129:687–90.
18. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA 1970;211:1854–5.
19. Jensen MK. Chromosome studies in patients treated with azathioprine and amethopterin. Acta Med Scand 1967;182:445–55.
20. Mancini RE, Larieri JC, Muller F, Andrada JA, Saraceni DJ. Effect of prednisolone upon normal and pathologic human spermatogenesis. Fertil Steril 1966;17:500–13.
21. Szabo I, Csaba I, Novak P, Drozgyik I. Single-dose glucocorticoid for prevention of respiratory-distress syndrome. Lancet 1977;2:243.
22. Szabo I, Csaba I, Bodis J, Novak P, Drozgyik J, Schwartz J. Effect of glucocorticoid on fetal lecithin and sphingomyelin concentrations. Lancet 1980;1:320.
23. Katz FH, Duncan BR. Entry of prednisone into human milk. N Engl J Med 1975;293:1154.
24. McKenzie SA, Selley JA, Agnew JE. Secretion of prednisone into breast milk. Arch Dis Child 1975;50:894–6.
25. Ost L, Wettrell G, Bjorkhem I, Rane A. Prednisolone excretion in human milk. J Pediatr 1985;106:1008–11.
26. Greenberger PA, Odeh YK, Frederiksen MC, Atkinson AJ Jr. Pharmacokinetics of prednisolone transfer to breast milk. Clin Pharmacol Ther 1993;53:324–8.
27. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
    
    

Q&A about Prednisone

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