ETRETINATE

Fetal Risk Summary

Etretinate, an orally active synthetic retinoid and vitamin A derivative, is used for the treatment of severe recalcitrant psoriasis. It is contraindicated in pregnant women and in those likely to become pregnant. Following oral administration, etretinate is stored in subcutaneous fat and is slowly released over a prolonged interval (1,2). In some patients after chronic therapy, detectable serum drug levels may occur up to 2.9 years after treatment has been stopped (2,3). Due to this variable excretion pattern, the exact length of time that pregnancy must be avoided after discontinuing treatment is unknown (2,3).

Like other retinoids (see also Isotretinoin and Vitamin A), etretinate is a potent animal teratogen (4). Data accumulated since release of this drug now indicate that it must be considered a human teratogen as well (1,2 and 3,5,6).

As of June 1986, a total of 51 pregnancies had occurred during treatment with etretinate (1,7,8). Of these pregnancies, 23 were still ongoing at the time of the reports and were unable to be evaluated (1). In the remaining 28 cases, 17 resulted in normal infants and three were normal fetuses after induced abortion. Skeletal anomalies were evident in eight cases: three liveborns, one stillbirth at 5 months, and four induced abortions. In addition, marked cerebral abnormalities, including meningomyeloceles, were observed in the stillborn and in three of the aborted fetuses.

A 1988 correspondence listed 22 documented etretinate exposures during pregnancy in West Germany as of September 1988 (9). The outcomes of these pregnancies were six induced abortions (no anomalies observed), four spontaneous abortions (no anomalies observed), six normal infants, and six infants with malformations (9).

Fifty-three pregnancies are known to have occurred following discontinuance of etretinate therapy (1,10). Malformations were observed in a fetus and an infant among the 38 pregnancies with known outcomes. In one case, a 22-year-old woman, treated intermittently over 5 years, became pregnant 4 months after etretinate therapy had been stopped (1,11,12). Serum concentrations of etretinate and the metabolite, etretin, were 7 ng/mL and 8 ng/mL, respectively, during the 8th week of gestation (6 months after the last dose). Following induced abortion at 10 weeks' gestation, the fetus was found to have unilateral skeletal defects of the lower limb consisting of a rudimentary left leg with one toe, missing tibia and fibula, and a hypoplastic femur (11,12). Evaluation of the face, skull, and brain was not possible. The defect was attributed to etretinate.

The second case also involved a 22-year-old woman who conceived 51 weeks after her last dose of etretinate (10). Other than the use of metoclopramide at 8 weeks' gestation for nausea and vomiting, no other drug history was mentioned. A growth-retarded (2850 g, 46 cm long, 3rd percentile) female infant was delivered by cesarean section at 38 weeks' gestation. Multiple congenital anomalies were noted involving the central nervous system, head, face, and heart, which included tetralogy of Fallot, microcephaly, hair whorls, small mandible, asymmetrical nares, protruding ears with malformed antihelices, absent lobules, and enlarged, keyhole-shaped entrances to the external ear canals, strabismus, left peripheral facial nerve paresis, and poor head control. Etretinate was detected in the mother's serum 3.5 months after delivery, but the concentration was below the test's lower limit of accuracy (2 ng/mL). No etretinate was detected in the infant's serum. Etretinate was considered responsible for the defects based partially on the presence of the drug in the mother's serum, and the fact that the pattern of malformation was identical to that observed with isotretinoin, another synthetic retinoid. The author also concluded that women treated with etretinate should avoid conception indefinitely (10).

Some of the defects noted in the above infant are also components of the CHARGE (coloboma, heart defects, choanal atresia, retardation, genital [males only], and ear anomalies) association (13), but in a response, the author of the case immediately above noted that such a relationship does not exclude etretinate as the etiology of the defects (14). Others have questioned whether an indefinite recommendation to avoid pregnancy is practical or necessary (15,16). In West Germany, 2 years of conception avoidance are recommended followed by determination of serum levels of etretinate and its metabolites (16). In six women treated with etretinate from 4–78 months, plasma concentrations of the drug were detected after 12 months in three patients (4, 8, and 8 ng/mL) and after 18 months in one patient (10 ng/mL) (16). Two women had no measurable etretinate 12 and 14 months after stopping therapy. The metabolites, acitretin and cis-acitretin, were detectable in two women (at 8 and 18 months) and five women (at 8–18 months).

The range of malformations, as listed by the manufacturer, includes meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactylies, absence of terminal phalanges, malformations of hip, ankle and forearm, low-set ears, high palate, decreased cranial volume, and alterations of the skull and cervical vertebrae (2).

Pronounced jaundice with elevations of the transaminase enzymes, glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase, was observed in an otherwise normal male newborn following in utero exposure to etretinate (17). The cause of the liver pathology was unknown. No other abnormalities were observed, and the infant was normal at 5 months of age.

One source has suggested that male patients treated with etretinate should avoid fathering children during treatment; if this does occur, ultrasound of the fetus is indicated (18). Although there is no evidence that etretinate adversely affects sperm, and even if it did, that this could result in birth defects, the authors defended their comment as practicing “defensive” medicine (19,20).

Breast Feeding Summary

It is not known if etretinate is excreted into human milk (2). The closely related retinoid, vitamin A, is excreted (see Vitamin A) and the presence of etretinate in breast milk should be expected. The manufacturer considers use of the drug during lactation to be contraindicated due to the potential for adverse effects (2).

References

1. Orfanos CE, Ehlert R, Gollnick H. The retinoids: a review of their clinical pharmacology and therapeutic use. Drugs 1987;34:459–503.
2. Roche Scientific Summary. The clinical evaluation of Tegison. Roche Laboratories, Division of Hoffmann-La Roche, Inc, 1986.
3. Anonymous. Etretinate approved. FDA Drug Bull 1986;16:16–7.
4. Kamm JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 1982;6:652–9.
5. Anonymous. Etretinate (Tegison) for skin disease. Drug Ther Bull 1983;21:9–11.
6. Anonymous. Etretinate for psoriasis. Med Lett Drugs Ther 1987;29:9–10.
7. Happle R, Traupe H, Bounameaux Y, Fisch T. Teratogenicity of etretinate in humans. Dtsch Med Wochenschr 1984;109:1476–80.
8. Rosa FW, Wilk AL, Kelsey FO. Teratogen update: vitamin A congeners. Teratology 1986;33:355–64.
9. Hopf G, Mathias B. Teratogenicity of isotretinoin and etretinate. Lancet 1988;2:1143.
10. Lammer EJ. Embryopathy in infant conceived one year after termination of maternal etretinate. Lancet 1988;2:1080–1.
11. Grote W, Harms D, Janig U, Kietzmann H, Ravens U, Schwarze I. Malformation of fetus conceived 4 months after termination of maternal etretinate treatment. Lancet 1985;1:1276.
12. Kietzmann H, Schwarze I, Grote W, Ravens U, Janig U, Harms D. Fetal malformation after maternal etretinate treament of Darier's disease. Dtsch Med Wochenschr 1986;111:60–2.
13. Blake KD, Wyse RKH. Embryopathy in infant conceived one year after termination of maternal etretinate: a reappraisal. Lancet 1988;2:1254.
14. Lammer E. Etretinate and pregnancy. Lancet 1989;1:109.
15. Greaves MW. Embryopathy in infant conceived one year after termination of maternal etretinate: a reappraisal. Lancet 1988;2:1254.
16. Rinck G, Gollnick H, Orfanos CE. Duration of contraception after etretinate. Lancet 1989;1:845–6.
17. Jager K, Schiller F, Stech P. Congenital ichthyosiforme erythroderma, pregnancy under aromatic retinoid treatment. Hautarzt 1985;36:150–3.
18. Ellis CN, Voorhees JJ. Etretinate therapy. J Am Acad Dermatol 1987;16:267–91.
19. Katz R. Etretinate and paternity. J Am Acad Dermatol 1987;17:509.
20. Ellis CN, Voorhees JJ. Etretinate and paternity (reply). J Am Acad Dermatol 1987;17:509.