TRIENTINE

Fetal Risk Summary

Trientine is a chelating agent used for the removal of excess copper from the systems of patients with Wilson's disease who either cannot tolerate penicillamine or who have developed penicillamine resistance. The drug is available in the United States only as an orphan drug.

In studies with pregnant rats, trientine was teratogenic in doses similar to those used in humans (1,2,3,4,5 and 6) . The frequency of fetal resorptions and malformations, including hemorrhage and edema, was directly related to the decrease in fetal copper concentrations.

Data on the human placental transfer of trientine have not been located, but the molecular weight of the compound (about 219 for the dihydrochloride salt) suggests that drug in the maternal serum reaches the fetus.

Only one Reference has been located that describes the use of trientine in human pregnancy (7). Seven women with Wilson's disease, treated with the chelating agent, were observed through 11 pregnancies. At the time of conception, the average duration of therapy had been 5 years (range 2–3 weeks to 9 years). Therapy was continued throughout pregnancy in seven cases, interrupted in the 2nd trimester of one because of inability to obtain the drug, and apparently was discontinued in the final few weeks of still another because of nausea not related to trientine (7). One woman underwent a therapeutic abortion at 10 weeks' gestation and one spontaneously aborted a normal male fetus, together with a copper contraceptive coil, at 14 weeks' gestation.

Of the pregnancies ending with a live infant, there were four males, four females, and one infant whose sex was not specified. The mean birth weight of the full-term infants was 3263 g. Two of the infants were delivered prematurely, one male at 36 weeks (2400 g) and one female at 31 weeks (800 g). The latter infant had an isochromosome X, but both parents had normal X chromosomes. No other abnormalities were observed in the infants at the time of birth. Because copper deficiency is thought to be teratogenic, the author concluded that the exposed fetuses did not become copper depleted (7). Evidence supporting this conclusion was obtained from the mean ceruloplasmin concentration of cord blood, 9.9 mg/dL, which was nearly identical to nontreated controls (10 mg/dL) (7). Additional studies, however, are needed before this conclusion can be accepted with confidence. Except for slow progress at 3 months in the infant with the isochromosome X, development in the other children was normal during follow-up evaluations ranging from 2 months to 9 years.

Breast Feeding Summary

No reports describing the use of trientine during lactation have been located. The molecular weight (about 219 for the dihydrochloride salt), however, is low enough that passage into milk should be anticipated. The effect of this exposure on a nursing infant is unknown.

References

1. March L, Fraser FC. Chelating agents and teratogenesis. Lancet 1973;2:846.
2. Keen CL, Mark-Savage P, Lonnerdal B, Hurley LS. Low tissue copper and teratogenesis in rats resulting from D-penicillamine (abstract). Fed Proc 1981;40:917.
3. Keen CL, Cohen NL, Lonnerdal B, Hurley LS. Low tissue copper and teratogenesis in trientine-treated rats. Lancet 1982;1:1127.
4. Keen CL, Lonnerdal B, Cohen NL, Hurley LS. Drug-induced Cu deficiency: a model for Cu deficiency teratogenicity (abstract). Fed Proc 1982;41:944.
5. Cohen NL, Keen CL, Lonnerdal B, Hurley LS. Low tissue copper and teratogenesis in triethylenetetramine-treated rats (abstract). Fed Proc 1982;41:944.
6. Product information. Syprine. Merck, 2000.
7. Walshe JM. The management of pregnancy in Wilson's disease treated with trientine. Q J Med 1986;58;81–7.