Drugs in Pregnancy and Lactation Name: TRETINOIN (TOPICAL)
Class: Vitamin
Risk Factor:    CM

Fetal Risk Summary

Tretinoin (all-trans retinoic acid; retinoic acid; vitamin A acid) is a retinoid and vitamin A (retinol) metabolite used topically for the treatment of acne vulgaris and other skin disorders and systemically in the treatment of acute promyelocytic leukemia (see Tretinoin [Systemic]). Like other retinoids, the drug is a potent teratogen following exposure in early pregnancy (see also Etretinate, Isotretinoin, and Vitamin A), producing a pattern of birth defects termed retinoic acid embryopathy (central nervous system, craniofacial, cardiovascular, and thymic anomalies). The teratogenic effect of tretinoin is dose dependent in that an endogenous supply of retinoic acid is required for normal morphogenesis and differentiation of the embryo, including a role in physiologic developmental gene expression (1).

Low serum concentrations or frank deficiency of vitamin A and all-trans retinoic acid is also teratogenic. Recent studies have shown that inhibition of the conversion of retinol to retinoic acid or depletion of retinol may be involved in the teratogenic mechanisms of such agents as ethanol (2,3,4,5 and 6) and some anticonvulsants (7).

The extensive literature on the teratogenicity of tretinoin in various animal species has been summarized in a number of sources (8,9,10,11 and 12) . The latter Reference has particular application to the study of the teratogenic effects of tretinoin because it was an examination of the toxicity of very small doses of this compound at presomite stages in mouse embryos, thought to be the most sensitive period for retinoid-induced teratogenesis (12). An increasing incidence of severe microphthalmia, anophthalmia, and iridial colobomata was produced as the dose was increased from 0 to 1.25 mg/kg. These doses were much less than those typically used for reproductive toxicity testing at later gestational periods. Slightly higher threshold doses produced exencephaly (2.5 mg/kg) and marked craniofacial defects (7.5 mg/kg) representative of the holoprosencephaly-aprosencephaly spectrum (12).

When used topically, the teratogenic risk of tretinoin had been thought to be close to 0 (13). According to one source, no cases of toxicity had been reported after nearly 20 years of use (13). In support of this, it has been estimated that even if maximal absorption (approximately 33%) occurred from a 1-g daily application of a 0.1% preparation, this would only result in about one-seventh of the vitamin A activity received from a typical prenatal vitamin supplement (14). One Reference source stated that 80% of a 0.1% formulation in alcohol remained on the skin's surface, but when a 0.1% ointment was applied to the back with a 16-hour occlusive dressing, only 50% of the drug remained on the skin surface and 6% was excreted in the urine within 56 hours (15). Authors of a 1992 Reference reviewed the teratogenicity of vitamin A and its congeners, including tretinoin, but did not derive a conclusion on the safety of the drug following topical use (16), most likely because of the lack of studies with the drug in pregnancy.

In two brief reports, congenital malformations in newborns whose mother's were using tretinoin during the 1st trimester were described (17,18). The first case involved a woman who had used tretinoin cream 0.05% during the month before her last menstruation and during the first 11 weeks of pregnancy (17). Her term, growth-retarded (weight 2620 g, <3rd percentile; length 49 cm, 25th percentile; head circumference 32.5 cm, 3rd percentile), female infant had a crumpled right hypoplastic ear and atresia of the right external auditory meatus, a pattern of ear malformation identical with that observed with vitamin A congeners (17). The remainder of the examination was normal, including the eyes, cerebral computed tomography, and chromosomal analysis. The second report contained the description of the female infant of a woman who had used an over-the-counter alcohol-based liquid preparation of 0.05% tretinoin for severe facial acne (18). The infant had multiple congenital defects consisting of supraumbilical exomphalos, a diaphragmatic hernia, a pericardial defect, dextroposition of the heart, and a right-sided upper limb-reduction defect.

The results of a prospective survey involving 60 completed pregnancies exposed to tretinoin early in pregnancy were presented in a 1994 abstract (19). From these pregnancies there were 53 liveborns (1 set of twins), 3 lost to follow-up, 4 spontaneous abortions, and 1 elective termination. No major malformations characteristic of retinoic acid embryopathy were observed except for one case in which the mother had also taken isotretinoin.

Among 25 birth defect cases with 1st-trimester exposure to tretinoin reported to the FDA between 1969 and 1993, 5 were cases of holoprosencephaly (20). Six other cases of holoprosencephaly involved other vitamin A derivatives: isotretinoin (N=4), etretinate (N=1), and megadose vitamin A (N=1). In contrast, among 8,700 non-retinoid-exposed birth defect reports to the FDA, only 19 involved suspected holoprosencephalies (20). However, other data from 1,120 apparent 1st-trimester exposures to tretinoin were examined. Among the 49 birth defects observed (the expected incidence), no cases of holoprosencephaly were seen. Although it is speculation, the contrasting findings in the above two reports (19,20) on early pregnancy tretinoin exposure may reflect (a) fetal exposure to different doses of tretinoin at the critical times from the use of higher maternal doses or from enhanced systemic absorption, or (b) biased reporting of adverse pregnancy outcomes to the FDA.

A 1993 report summarized data gathered from the Group Health Cooperative of Puget Sound, Washington, involving 1st-trimester exposure to topical tretinoin and congenital malformations (21). A total of 215 women who had delivered live or stillborn infants and who were presumed to have been exposed to the drug in early pregnancy were compared with 430 age-matched nonexposed controls of live or stillborn infants delivered at the same hospitals. A total of 4 (1.9%) infants in the exposed group had major anomalies compared with 11 (2.6%) in the controls, a relative risk of 0.7 (0.2–2.3) (21). The defects observed in the exposed group of infants were hypospadias, undescended or absent testicles, metatarsus adductus, and esophageal reflux. The three stillborn infants in the exposed group were all associated with umbilical cord accidents. The authors concluded that these data provided no evidence for a relationship between topical tretinoin and the congenital abnormalities normally observed with other vitamin A congeners or for an increased incidence of defects compared with data from women not using tretinoin (21).

A brief 1997 report described a prospective, observational, controlled study that compared the pregnancy outcomes of 94 women who had used topical tretinoin during pregnancy with 133 women not exposed to topical tretinoin or other known human teratogens (22). Both groups were composed of pregnant women who had contacted a teratology information service between 1988 and 1996. No differences between the groups were found for the number of live births, miscarriages, elective terminations, major malformations, duration of pregnancy, cesarean sections, birth weight (after exclusion of one baby weighing 5396 g in the control group), and low birth weight. Two live-born infants from the tretinoin-exposed group had major birth defects: a bicuspid aortic valve in one and dysplastic kidneys in one. Neither of the defects is consistent with retinoic-acid embryopathy (22). Malformations in the four infants from the control group were congenitally dislocated hip in two, aortic valvular stenosis in one, and inperforate anus in one.

In summary, elevated serum concentrations of all-trans retinoic acid in early gestation are considered teratogenic in humans. Because of its relatively poor systemic absorption (if occlusive dressings are not used) after topical administration, however, tretinoin is not thought to present a significant fetal risk. Congenital malformations have been reported following topical use of this compound and, although a causal association has not been established, may reflect (a) greater-than-normal fetal exposure from higher-than-usual maternal doses or enhanced systemic absorption or (b) biased reporting of adverse outcomes. Most of the evidence, however, indicates that topical tretinoin does not increase the risk for congenital malformations.

Breast Feeding Summary

Vitamin A and, presumably, tretinoin (all-trans retinoic acid) are natural constituents of human milk. No data are available on the amount of all-trans retinoic acid excreted into milk following topical use. Although other retinoids are excreted (see Vitamin A), the minimal absorption that occurs after topical application of tretinoin probably precludes the detection of clinically significant amounts in breast milk from this source.

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References

  1. Morriss-Kay G. Retinoic acid and development. Pathobiology 1992;60:264–70.
  2. Keir WJ. Inhibition of retinoic acid synthesis and its implications in fetal alcohol syndrome. Alcohol Clin Exp Res 1991;15:560–4.
  3. Pullarkat RK. Hypothesis: prenatal ethanol-induced birth defects and retinoic acid. Alcohol Clin Exp Res 1991;15:565–7.
  4. Duester G. A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. Alcohol Clin Exp Res 1991;15:568–72.
  5. Dreosti IE. Nutritional factors underlying the expression of the fetal alcohol syndrome. Ann NT Acad Sci 1993;678:193–204.
  6. DeJonge MH, Zachman RD. The effect of maternal ethanol ingestion on fetal rat heart vitamin A: a model for fetal alcohol syndrome. Pediatr Res 1995;37:418–23.
  7. Fex G, Larsson K, Andersson A, Berggren-Sφderlund M. Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate. Possible relation to teratogenicity. Arch Toxicol 1995;69:572–4.
  8. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:555–62.
  9. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:370–3.
  10. Sanders DD, Stephens TD. Review of drug-induced limb defects in mammals. Teratology 1991;44:335–54.
  11. Apgar J, Kramer T, Smith JC. Retinoic acid and vitamin A: effect of low levels on outcome of pregnancy in guinea pigs. Nutr Res 1994;14:741–51.
  12. Sulik KK, Dehart DB, Rogers JM, Chernoff N. Teratogenicity of low doses of all-trans retinoic acid in presomite mouse embryos. Teratology 1995;51:398–403.
  13. Kligman AM. Question and answers: is topical tretinoin teratogenic? JAMA 1988;259:2918.
  14. Zbinden G. Investigations on the toxicity of tretinoin administered systemically to animals. Acta Derm Venereol (Stockh) 1975;Suppl 74:36–40.
  15. American Hospital Formula Service. Drug Information 1996. Bethesda, MD: American Society of Health-System Pharmacists, 1996:2608–10.
  16. Pinnock CB, Alderman CP. The potential for teratogenicity of vitamin A and its congeners. Med J Aust 1992;157:804–9.
  17. Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin cream. Lancet 1992;339:687.
  18. Lipson AH, Collins F, Webster WS. Multiple congenital defects associated with maternal use of topical tretinoin. Lancet 1993;341:1352–3.
  19. Johnson KA, Chambers CD, Felix R, Dick L, Jones KL. Pregnancy outcome in women prospectively ascertained with Retin-A exposures: an ongoing study (abstract). Teratology 1994;49:375.
  20. Rosa F, Piazza-Hepp T, Goetsch R. Holoprosencephaly with 1st trimester topical tretinoin (abstract). Teratology 1994;49:418–9.
  21. Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders. Lancet 1993;341:1181–2.
  22. Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimester exposure to topical tretinoin: prospective cohort study. Lancet 1997;350:1143–4.

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