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Effects on developmental toxicity

Description of key information
Prednisolone appeared to induce cleft palate if used in the first trimester of pregnancy.
Additional information

The induction of abnormal palatal development by three glucocorticoids, prednisolone, triamcinolone acetonide and hydrocortisone was evaluated in rat fetuses. Pregnant rats were injected subcutaneously with prednisolone (12.5 -100 mg/kg/day) on days 14 and 15 of gestation. These females were humanely killed on day 20 of gestation and viable fetuses were inspected for palatal abnormalities. The frequencies of cleft palate were significantly higher in the group treated with 100 mg/kg/day prednisolone (10.6%) than the control frequency of 0%. Prednisolone shows an ED50 value of 70 mg/kg/day. Other developmental abnormalities including omphalocele and general edema, late resorption, and growth retardation were induced by prednisolone. (Watanabe, C. et al.1995)

In a study to Sprague-Dawley rats, groups of 27 and 29 pregnant female were given daily oral doses of 0, 3, 30, or 100 mg/kg bw/day from day 6 to 15 of gestation. Two further groups were administered with 200 mg/kg bw/day causing severe maternal toxicity. Doses of 30 mg/kg bw/day and above caused increased embryolethality and reduced foetal weight. At 30 mg/kg bw/day two (out of 344) fetuses were malformed; one with cleft palate and one with omphalocele. (Fritz, H. et al. 1990)

Pregnant Holtzman rats were injected subcutaneously with anti-inflammatory drugs from day 12 to15 of gestation. Cleft palate was not induced by prednisolone even by daily doses ranging from 8-75 mg. Similar experiments were performed on A/J mice. The possible significance of these experiments in relation to testing potential teratogens and to the mechanism of palate closure is discussed in the article.

This work underscore as the teratogenic action of a glucocorticoid is unpredictable between species. If this hypotesis is true it becames pointless to rest for teratogenicity of drugs in rodents, since the only purpose of such testing is to extrapolate to man. Such extrapolation is very provisional at best. Thus, a single genetic background is not sufficient to evaluate the teratogenic potential of a drug. (Walker, B.E. 1971)

Intramuscular injections of prednisolone to New Zeland White rabbits were carried out to investigate the induction of cleft palate. Prednisolone was administered at doses of 1, 1.5, 2, 3, 4, or 8 mg /day from day 13 to 16 of gestation. No cases of cleft palate were observed in the foetusesfrom dams receiving 1 mg/day. Frequency of cleft palate increased with increasing dose levels from 1.5 to 4 mg/day until the point of complete litter resorption was reached at 8 mg/day. (Walker, B.E. 1967)

Prednisolone given 0.5 mg daily to A-JAX mice during mid-pregnancy produced a 77% incidence of cleft palate in the offspring. (Pinsky, L. et al.1965)

The effect of prenatal administration in hamster of different doses of prednisolone on the fetus and its palatal development was studied. Pregnant females were treated by a singular intramuscular injection of 7 to 20 mg/kg bw on day 11 of gestation. A dose-related incidence of frequency of cleft palate and the degree fetal growth retardation was observed. At 10 mg/kg bw was observed 93% incidence of cleft palate to reach 100% at 15 mg/kg bw. Moreover, at 20 mg/kg bw the rate of resorption was significantly higher than that of the control. (Shah, R.M. et al. 1976)

Swiss ICR:Ha albino pregnant mice were treated with prednisolone to evaluate the incidence of induced dead embryos, resorptions and cleft palate. The females received a single 50, 100, 200, or 330 mg/kg dose by intramuscular injection. From 100 to 330 mg/kg an increase of embryos resorptions was observed. The results demonstrate that prednisolone did not produce any increases in cleft palate even when administered at level up to 200 mg/kg. Prednisolone did produce consistent significant increase in cleft palate when administered in day 10 at 330 mg/kg. (Zawoiski, E.J. 1980)

Pregnant CD-1 mice were treated by direct application to eye of the solution or the suspension of prednisolone five times per day on gestation days 10 through 13. Ocularly applied prednisolone is adsorbed sistemically in sufficient quantity to produce teratogenic effects in mouse fetuses. The teratogenic effects observed were cleft palate and sex organ anormalities. When compared to control, the incidences of cleft palates were significantly higher (p<0.05) in all dosages reaching the plateau, already at the medium dose concentration, of 47% cleft palate. Ophthalmically applied prednisolone did produce incidences of cleft palate comparable to those produced by prednisolone administered intramuscularly or subcutaneously. (Ballard, P.D. et al. 1977)

Weigh of evidence studies:

CASE REPORT STUDY - The cause of risk to the fetus appears to be that of failure of placental function, manifesting itself either as a chronic process with a small fetus or as acute hypoxia in labour. This effect is apparently a direct result of prednisolone, since fetal mortality in the control group was low. The effect is not a disturbance of fetal adrenal function, since none of the babies gave clinical evidence of adrenocortical insufficiency. Experimental work suggests that placentation is damaged by glucocorticoids; Blackburn et al. (1965) found that the administration of prednisolone to pregnant rats inhibited placental growth, caused morphological changes resembling premature ageing of the placenta, and significantly increased the incidence of intrauterine deaths. The high incidence of fetal death and fetal risk attributable to a placental fault in our series suggest that a similar change may occur in pregnant women. (Warrell, D.W. et al. 1968)

CASE REPORT STUDY - From 18 case reports, there were 26 exposed pregnancies of which 7 (27%) ended with malformed offspring (higher than the usually reported population frequency of about 3%). Among them, 4 (15%) were cleft palate (Doig and Coltman, 1956; Bongiovanni and McPadden, 1960; Harris and Ross, 1956). that is, they may have been more likely to be reported because the association with cleft palate in mice was known. The other malformations were bilateral nuclear cataract, gastroschisis, and hydrocephalus. This fact could signify a teratogenic effect, or result from reporting bias.

In addition, they reviewed 17 reported series of 457 mothers exposed to corticosteroids in the first trimester. In this group, 16 (3.5%) of the offsprings were malformed, rates not higher than the rates observed in the general population. (Fraser, F.C. et al. 1995)

Prednisolone was classified in the FDA pregnancy category C. Risk factor D if used in the 1st trimester.

The Michigan Medicaid surveillance study surveyed 143 newborns exposed to prednisolone of completed pregnancies conducted from 1985 and 1992. Newborns were exposed to prednisolone in the 1st trimester of pregnancy (Rosa, F., personal communication, FDA, 1993). Observed versus expected major malformations was 11/6 (7.7%). The data should support an association between prednisolone and congenital defects. (Briggs, G.G. et al. 2008)

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