Dermatologic Agent
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY 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, tretinoin is not thought to present a significant fetal risk. Because some absorption does occur, however, it is not possible to exclude a teratogenic risk (1). Congenital malformations, some of which are consistent with those observed in retinoic acid embryopathy, have been reported after topical use, but a causal association has yet to be established. The reports may reflect (a) greater-than-normal fetal exposure from higher-than-usual maternal doses or enhanced systemic absorption, or (b) selective reporting of adverse outcomes that are not caused by tretinoin. Until more data are available, however, the safest course is to avoid the use of tretinoin during pregnancy, especially in the 1st trimester. But if inadvertent exposure does occur during early pregnancy, the fetal risk, if any, appears to be very low.
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]). As with other retinoids, the drug is a potent teratogen after exposure in early pregnancy (see also Etretinate, Isotretinoin, and Vitamin A), producing a pattern of birth defects termed retinoic acid embryopathy (CNS, craniofacial, cardiovascular, and thymic anomalies). However, an endogenous supply of retinoic acid is required for normal morphogenesis and differentiation of the embryo, including a role in physiologic developmental gene expression. The teratogenic effect of retinoic acid is manifested when the levels are excessive (2).
Low serum concentration 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 (3–7) and some anticonvulsants (8).
Two manufacturers have stated that reproduction studies with topical tretinoin in animals are equivocal. In pregnant rats, daily doses >200 times the recommended human topical dose (RHTD) were associated with shortened or kinked tail. At 2000 times the RHTD, skeletal anomalies (humerus: short, bent; os parietale incompletely ossified) were observed. In rabbits, fetotoxicity was observed with doses 100 times the RHTD. Doses approximately 80 times the RHTD in pregnant rabbits were associated with domed head and hydrocephaly, anomalies that are typical of retinoid-induced malformations in this species. In addition, a dose 91 times the RHTD was also associated with an increased incidence of cleft palate (9). In contrast, other studies with topical tretinoin in rats and rabbits at doses 100–200 times the RHTD have not demonstrated a teratogenic effect (9,10).
A 1997 report described the developmental toxicity of topical and oral tretinoin in pregnant rats (11). Topical doses of ≥10 mg/kg/day (approximately 2000 times the RHTD) were not tolerated, causing severe local and systemic maternal toxicity. Maternal toxicity (reduced weight gain and food consumption) was also evident at doses of 2.5 mg/kg/day (approximately 500 times the RHTD) or more. A significant increase in the occurrence of supernumerary ribs was observed at this dose, a result thought to be nonspecific or maternally mediated. In contrast, oral tretinoin doses of 5 and 10 mg/kg/day were not maternally toxic, but were associated with an increased incidence of supernumerary ribs (5 mg/kg/day) and cleft palate (10 mg/kg/day). Based on these results, the investigators concluded that only the highest oral dose was teratogenic (11).
Dose-related maternal toxicity was observed in rabbits treated topically with tretinoin cream at dosages of 10 and 100 times the human clinical dose (500 mg of 0.05% cream in a 50-kg adult equals 0.005 mg/kg/day) based on body weight (12). Maternal endogenous plasma tretinoin levels were below the detection level (5 ng/mL) in all animals. After treatment, however, a few rabbits had detectable concentrations of retinoic acid, 13-cis-retinoic acid, or their metabolites. The maternal toxicity was associated with an increased incidence of abortions, resorptions, and reduced fetal body weight. Some significant (p ≤0.01) increases in malformations (open eyelids and cleft palate) and variations (nasal ossification, fused sternebrae, and irregular-shaped scapular alae) were observed. However, these were not considered to be tretinoin-related because they were not dose-related, and the litter incidences either did not differ significantly from those of controls or were within expected ranges for the species (12).
Additional literature on the teratogenicity of both systemic and topical tretinoin in various animal species has been summarized in several sources (13–17). The latter reference has particular application to the study of the teratogenic effects of tretinoin because it examined the toxicity of very small oral doses of this compound at presomite stages in mouse embryos, thought to be the most sensitive period for retinoid-induced teratogenesis (17). 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 (17).
When tretinoin is used topically, its teratogenic risk had been thought to be close to 0 (18). According to one source, no cases of toxicity had been reported after nearly 20 years of use (18). 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 result in only about one-seventh of the vitamin A activity received from a typical prenatal vitamin supplement (19). One 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 (20).
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 after topical use (21), most likely because of the lack of studies with the drug in pregnancy.
Five reports of congenital malformations in newborns whose mother’s were using tretinoin during the 1st trimester have been located (22–26). 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 (22). Her term, growth-restricted (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. The remainder of the examination was normal, including the eyes, cerebral computed tomography, and chromosomal analysis (22).
The second report described 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 (23). 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.
A 1998 case report described the pregnancy outcome of a woman who had used, before conception and during the first 2 months of gestation, a topical alcohol-based preparation of tretinoin 0.05% combined with benzoyl peroxide 2.5% for facial acne (24). Except for doxycycline (200 mg/ day) that had been taken for an unknown duration, she had no other exposures to medications or vitamins. An ultrasound examination at 5 months’ gestation detected hand and heart malformations. The female infant (2800 g; length 48 cm; normal karyotype 46,XX) was delivered at term with coarctation of the aorta, hypoplastic left hand, and small ear canals. The authors noted the similarity of some of the anomalies to those observed in retinoic acid embryopathy and speculated that the keratolytic action of benzoyl peroxide may have enhanced the cutaneous absorption of tretinoin. However, they also noted that any association between tretinoin and the birth defects may have been fortuitous (24).
Severe malformations were reported in a term, female infant whose mother had used tretinoin (0.05%) twice daily for facial acne before and throughout gestation (25). The defects were thought to be consistent with abnormal cranial neural crest cell migration. They included craniofacial defects (cleft palate and harelip, fused palpebral fissures, hypertelorism, a depressed nasal bridge, and deficient left naris) and CNS anomalies (disorganized rudimentary optic cup derivatives with optic tract dysgenesis, arrhinencephaly, agenesis of the corpus callosum, fornices and cingulate gyri, cerebellar hypoplasia, and aqueduct stenosis with hydrocephalus) (25).
The fifth case report involved a 4090-g term male infant who was born with absence of the right ear and external auditory canal (26). The mother had used tretinoin 0.025% topically on her face and over a large area of her back before conception and during the first 2–3 months of gestation. She took prenatal vitamins during pregnancy. The father was using isotretinoin before conception. Examinations at 16 and 20 months of age revealed a nonverbal infant with poor receptive language consistent with cognitive impairment. He had age-appropriate muscle strength, tone and bulk. There was a diminished optokinetic response and no oculovertibular response when rotating toward the right. Extensive examinations revealed cerebral calcification of the right posterior hemisphere, an overall reduction in the volume of the right cerebral hemisphere, a remote infarct in the deep basal ganglia, focal atrophy and encephalomalacia of the right parieto-occipital lobe. Marked abnormalities were noted in the posterior cerebral artery and some of its branches. Hypometabolism, sometimes severe, was observed in several regions of the brain, including the thalamus (26).
The results of a prospective survey involving 60 completed pregnancies exposed to tretinoin early in pregnancy were presented in a 1994 abstract (27). 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 (27).
Among 25 birth defect cases with 1st trimester exposure to tretinoin reported to the FDA from 1969 to 1993, 5 were cases of holoprosencephaly (28). 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 8700 nonretinoid-exposed birth defect reports to the FDA, only 19 involved suspected holoprosencephalies (28). Pregnancy outcomes from 1120 apparent 1st trimester tretinoin exposures were also 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 (27,28) 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) selective (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 (29). A total of 215 women who had delivered live or stillborn infants and were presumed to have been exposed to the drug in early pregnancy were compared with 430 age-matched nonexposed controls of women whose live or stillborn infants were delivered at the same hospitals. A total of 4 (1.9%) infants in the exposed group had major anomalies compared with 11 (2.6%) among the controls, a relative risk of 0.7 (95% confidence interval 0.2–2.3). The defects observed in the exposed 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 (29). The findings of this study were summarized in a review article on retinoids and teratogenicity (30).
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 (31). Both groups were composed of pregnant women who had contacted a teratology information service in the years from 1988 to 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 liveborn infants from the tretinoin-exposed group had major birth defects: a bicuspid aortic valve in one and dysplastic kidneys in one. Neither defect is consistent with retinoic acid embryopathy. Malformations in the four infants from the control group were congenitally dislocated hip in two, aortic valvular stenosis in one, and imperforate anus in one (31).
Several comments concerning the above study were made in a 1999 letter (32). The primary concern expressed was that the number of subjects enrolled in the study was too small to derive any conclusions as to the safety of tretinoin in the 1st trimester. The authors thought that the risk of certain birth defects, specifically cardiac anomalies and microtia, could not be excluded, and that the use of tretinoin in pregnancy was contraindicated (32).
BREASTFEEDING SUMMARY
Vitamin A and, presumably, tretinoin (all-trans retinoic acid) are natural constituents of human milk. There are no data available on the amount of all-trans retinoic acid excreted into milk after 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. Thus, use of tretinoin while breastfeeding does not appear to represent a significant risk to a nursing infant.
References
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