METHOXSALEN

Fetal Risk Summary

Methoxsalen (8-methoxypsoralen), available in oral capsules and as a topical lotion, is used as a photosensitizer in conjunction with long-wave UVA radiation (PUVA) for the symptomatic control of severe psoriasis. Reproductive toxicity testing of the agent in animals has not been conducted (1). Shepard reviewed a closely related compound, 5-methoxypsoralen (5-MOP), that was not teratogenic in pregnant mice given up to 500 mg/kg/day, but was teratogenic in rabbits (type of malformations not specified) fed 70 or 560 mg/kg/day (2).

Because PUVA treatments are mutagenic, investigators, in a 1991 report, described the pregnancy outcomes among 1,380 patients (892 men and 488 women) who had received the therapy (3). Of the men, 99 (11.1%) reported 167 pregnancies in their partners, whereas 94 (19.3%) of the women reported 159 pregnancies. Among the men, 34% (55 of 163; data missing for 4 pregnancies) received PUVA therapy near the time of conception. In the women, 20% (31 of 158; data missing for 1 pregnancy) received treatment at the time of conception or during pregnancy. The difference in the incidence of spontaneous abortions among those exposed (men 3.6% vs. women 12.9%) was thought to be related to reporting bias, but the total rate of abortions is no different from that expected in a nonexposed population. No congenital malformations were reported in the offspring of the exposed patients.

A 1993 publication described the outcome of 689 infants born before maternal PUVA treatment, 502 infants conceived and born after treatment, and 14 infants whose mothers had received the therapy during pregnancy (4). No difference among the three groups was noted in sex ratio, twinning, and mortality rate after birth. A significant increase in low-birth-weight infants was observed in those conceived and born after maternal treatment, an effect, the authors concluded, that may have resulted from the mother's disease. No congenital abnormalities were observed in the 14 infants exposed in utero to PUVA therapy. In the other two groups, 3.6% (25 of 689) and 3.2% (16 of 502) of the infants had congenital defects.

PUVA treatment occurred around the time of conception or during the 1st trimester of pregnancy (none treated after the 1st trimester) in 41 women identified by the European Network of Teratology Information Services (5). Of these cases, 32 were treated before conception and during the 1st trimester, 8 were treated only during the 1st trimester, and 1 stopped treatment 2 weeks before conception. The number of treatments was described as normal (two to three per week) in 27 cases, less than normal in 6 cases, greater than normal in 2, and unknown in 6 women. The maximum daily dose of methoxsalen was 40 mg. Four (10%) of the pregnancies terminated with a spontaneous abortion (a normal incidence), 6 were voluntarily terminated, 1 woman was lost to follow-up, and 31 infants (1 set of twins) were liveborn. Two of the infants had low birth weights (2120 g and 2460 g), but neither was attributable to the mother's therapy or to psoriasis. No malformations were observed at birth or in the neonatal period. The sample size in this study allowed the authors to exclude a 6-fold increase in the risk for all malformations (5).

In summary, although methoxsalen combined with UVA is mutagenic, carcinogenic, and cataractogenic in humans, it does not appear to be a significant human teratogen. However, the long-term effects of in utero exposure to methoxsalen, such as cancer, have not been studied but warrant investigation.

Breast Feeding Summary

No reports describing the use of methoxsalen during breast feeding have been located, nor is it known whether the drug is excreted into breast milk. Because the drug acts as a photosensitizer, breast feeding should be stopped and the milk discarded, probably for at least 24 hours (approximately 95% of a dose is excreted in the urine as metabolites within 24 hours [1]), if the drug is administered.

References

1. Product information. Oxsoralen. ICN Pharmaceuticals, 1995.
2. Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: Johns Hopkins University Press, 1992:257.
3. Stern RS, Lange R, Members of The Photochemotherapy Follow-up Study. Outcomes of pregnancies among women and partners of men with a history of exposure to methoxsalen photochemotherapy (PUVA) for the treatment of psoriasis. Arch Dermatol 1991;127:347–50.
4. Gunnarskog JG, Källén AJB, Lindelöf BG, Sigurgeirsson B. Psoralen photochemotherapy (PUVA) and pregnancy. Arch Dermatol 1993;129:320–3.
5. Garbis H, Eléfant E, Bertolotti E, Robert E, Serafini MA, Prapas N. Pregnancy outcome after periconceptional and first-trimester exposure to methoxsalen photochemotherapy. Arch Dermatol 1995;131:492–3.