Evaluation of the reproductive and developmental safety of cysteamine in the rat: Effects on female reproduction and early embryonic development

Abstract

Cystinosis is an autosomal recessive metabolic disease in which the amino acid cystine accumulates in lysosomes due to a defect in lysosomal cystine transport. Cystinosis in infancy is associated with poor growth, muscle wastage, and death at about age 10 due to kidney failure. Treatment with cysteamine and kidney transplantation enables cystinotic girls to reach reproductive age and to be healthy enough to permit pregnancy. It is not known whether exposure to cysteamine will have adverse effects on reproduction in the human. It is also possible that some of the complications seen in cystinotic children could be avoided if a pregnant woman carrying a cystinotic fetus were given cysteamine. However, this treatment is not likely to occur until therapeutic exposures to cysteamine are judged to present no increased risk to the human fetus. As part of a larger investigation assessing the reproductive and developmental safety of cysteamine (as phosphocysteamine) using the rat, the two studies reported herein were performed. The first, a dose-finding study, led to the selection of 150 mg/kg/day as the highest dose of cysteamine used for the second and primary focus of this report. The second study involved the exposure of female rats to cysteamine from premating through day 6.5 postconception and assessment of female fertility and early embryonic development. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. There were no clinical signs of maternal toxicity during the exposures of 2 to 5 weeks before successful mating. Animals in the 150 mg/kg/day group experienced a nonsignificant decrease in body weight gain during pregnancy to day 6.5 postconception, a significant increase in liver and spleen weights, and a significant increase in days to coitus--suggesting that a low level of toxicity was manifested. However, there were no adverse effects on reproductive performance with respect to conception and early embryonic development.

Pregnancy in cystinosis patients with chronic kidney disease: A European case series

“…In our series, some patients stopped the treatment before conception and others after diagnosis of pregnancy. An evaluation of the effects of cysteamine on early development in rats revealed no adverse effects on conception and early embryonic development 12 . As the time to conception can be protracted and because of the lack of congenital abnormalities in babies whose mothers stopped cysteamine at conception, we suggest stopping cysteamine treatment only on confirmation of pregnancy.…”

“…An evaluation of the effects of cysteamine on early development in rats revealed no adverse effects on conception and early embryonic development. 12 As the time to conception can be protracted and because of the lack of congenital abnormalities in babies whose mothers stopped cysteamine at conception, we suggest stopping cysteamine treatment only on confirmation of pregnancy. Only one patient not taking cysteamine during that period breast fed her two babies.…”

Effects of pre- and postnatal cysteamine exposure on renal function in the rat

“…Reversible liver dysfunction and leukopenia may also occur [6,7]. Recent reports [8,9] of adverse effects on the developing fetus after treatment of the pregnant rat with cysteamine have raised concerns about the safety of cysteamine during human pregnancy. These studies demonstrated a doseresponse relationship for adverse fetal outcome, including cleft palate, kyphosis, intrauterine growth retardation, and fetal death.…”