Antidote/Chelating Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Two reports have described the use of succimer during human pregnancy. The chelating agent has produced fetotoxicity and teratogenicity in mice and fetotoxicity in rats. These toxic effects often occurred at oral doses ≤10 times the human dose (weight basis). In addition, succimer-induced modulation of adult female rat immune function has been demonstrated. The exact mechanism of the animal developmental toxicity is unknown but appears to result from disturbances in mineral metabolism, especially that of zinc and copper. Therefore, if succimer is used in human pregnancy, the effects on maternal and fetal mineral metabolism—in particular, of zinc and copper—should be evaluated (1).
FETAL RISK SUMMARY
The heavy metal chelating agent succimer (meso-2,3-dimercaptosuccinic acid [DMSA]) is indicated for the treatment and prophylaxis of lead poisoning in pediatric patients (2). The drug has also been used as an antidote for the treatment of arsenic, mercury, and cadmium poisoning (3). Succimer has no significant effect on the urinary elimination of iron, calcium, or magnesium but doubles the excretion of zinc (2). After oral administration, approximately 60% is absorbed systemically from an initial dose of 30 mg/kg/day (1050 mg/m2/day) with an apparent elimination half-life of approximately 2 days.
In addition to the animal reproductive data provided by the manufacturer (2), a number of published animal studies have described the effect of succimer on the fetus (3–12). In pregnant rats, doses of 100–1000 mg/kg/day administered orally on gestational days 6–15 were not teratogenic but did produce maternal toxicity (decreased weight gain) (3). At pregnancy termination on day 20, fetal toxicity, characterized by increased early resorptions, postimplantation losses, and reduced fetal body weight per litter, was evident at all doses. The no-observable-effect level (NOEL) was <100 mg/kg/day (3).
In another portion of the above study, the concentrations of five minerals (calcium, magnesium, zinc, copper, and iron) were measured in maternal and fetal tissues (4). Marked alterations were observed on the mineral concentrations in the fetuses. These effects suggested that the fetal toxicity noted was partially due to changes in mineral metabolism (4).
Succimer was teratogenic and fetotoxic when SC doses were given to pregnant mice during organogenesis (days 6–15 of gestation) at doses of 410–1640 mg/kg/day (2,5). At the maximum dose, maternal toxicity (reduced weight gain) was evident (5). Significant embryo and fetal toxicity, as evidenced by an increased incidence of resorptions and stunting, and a decrease in the number of live fetuses per litter, were observed at 1640 mg/kg/day. At 820 mg/kg/day, significant decreases in fetal weight and length were noted. A dose relationship was found for structural defects, including significant increases (compared with controls) in gross external defects (hematomas in the facial area, exencephaly, and micrognathia), internal soft tissue defects (hydrocephaly, small thoracic cavities, and brain defects), and skeletal variations (decreased ossification, hypoplasia of the mandible, and irregular-shaped ribs). The no-effect dose for defects was 410 mg/kg/day (5).
In continuation of the above study, pregnant mice were given oral succimer (200–800 mg/kg/day) from gestational day 14 through postnatal day 21 (weaning) (6). No maternal toxicity was observed at any dose. Adverse effects were observed only in the offspring exposed during lactation to the highest maternal dose. The effects observed in the nursing pups included significant decreases in body weight and a corresponding increase in relative brain weight (brain weight/body weight). The NOEL for adverse effects in the nursing pups was >400 mg/kg/day (6).
The type of developmental toxicity observed in mice suggested to some investigators that the toxicity may have been related to an interaction between succimer and zinc (5). However, in a subsequent report, no consistent changes could be demonstrated in mice fetal tissue levels of zinc, iron, calcium, or magnesium (7). Moreover, supplemental zinc did not protect the fetuses. Disturbance of maternal–fetal copper metabolism may have been related to the developmental toxicity because dose-dependent decreases in fetal liver copper levels were observed (7).
A 1991 report examined the efficacy of succimer to protect mice fetuses from the toxicity and teratogenicity of an intraperitoneal (IP) dose (12 mg/kg) of sodium arsenite administered to pregnant mice on day 10 of gestation (8). In the dose-finding portion of the study, succimer SC doses of 80, 160, and 320 mg/kg were given immediately after sodium arsenite injection. An increasing protective effect was noted with an increasing succimer dose. The effect of the time interval between IP injection of sodium arsenite and injection of succimer was then studied. A single SC dose of succimer (320 mg/kg) was given to pregnant mice at various times up to 12 hours after a dose of sodium arsenite. Significant reductions in arsenite-induced embryo toxicity and teratogenicity were achieved only when succimer was administered within 1 hour of the arsenite dose (8).
Using a similar study design, the above investigators examined the effect of succimer in protecting fetal mice from the toxicity and teratogenicity of dibasic sodium arsenate (9). Sodium arsenate is the most common form of inorganic arsenic in the environment and is less fetotoxic than sodium arsenite (8,9). As in the above study, the investigators demonstrated a dose-related protective effect of succimer at SC doses of 37.5, 75, and 150 mg/kg administered at four successive time intervals (2, 24, 48, and 72 hours) after IP injection of dibasic sodium arsenate (45 mg/kg) (9).
A 1978 study in pregnant rats demonstrated that daily administration of succimer was effective in reducing methylmercury concentrations in neonatal rat brains (10). A 40-mg oral dose was more effective (70% reduction in methylmercury) than a 20-mg dose (50% reduction). In a later study with pregnant mice, a dose-related protective effect from methylmercury-induced embryolethality and teratogenicity was demonstrated with the maximum protection achieved with an SC dose of 320 mg/kg/day (11).
The effect on the immune function of female rats exposed to succimer in utero was described in a 1999 report (12). Pregnant rats were administered lead acetate (250 ppm) in drinking water from 2 weeks before mating until parturition. Succimer (60 mg/kg/day), given orally from days 6–21 of gestation, significantly lowered the blood lead levels in both the dams and embryos. Several lead-induced changes in 13-week-old female offspring were reversed by the chelating agent (succimer-induced changes in parentheses), including body weight (increased), relative spleen weight (decreased), interferon γ (increased), and interleukin-4 (decreased). However, succimer alone affected immune function in the female offspring by decreasing the delayed-type hypersensitivity response and increasing interleukin-2 production. Therefore, succimer treatment during gestation did reverse some of the lead-induced immunotoxicity but also caused subsequent adult immunomodulation (12).
It is not known if succimer crosses the human placenta. The molecular weight (about 182) is low enough that fetal exposure should be expected. The studies cited above suggest that succimer crosses the placenta in mice and rats.
A 2001 case report described an 18-day course of oral succimer for lead poisoning at about 29–32 weeks’ gestation (13). There was no effect on the woman’s blood lead concentrations (44.0 mcg/dL before chelation and 43.9 mcg/ dL after treatment). She gave birth at 37 weeks’ to a 3.04-kg, female infant with Apgar scores of 8 and 9. At birth, the mother’s blood lead level was 57.6 mcg/dL, whereas the cord blood lead concentration was 126 mcg/dL. The source of the lead in the mother was not found, even though an extensive search for the source was conducted. The infant was treated with chelation therapy and, although the concentrations remained elevated, her appearance and behavior were normal at 6.5 months of age (13).
One pregnant woman, in a series of seven, was treated with succimer for lead poisoning in a 2003 report (14). The source of the lead in most cases was the ingestion of pica (soil/clay-based substances). No lead-induced congenital defects were noted in the infants, but all received chelation therapy in the neonatal period (14).
BREASTFEEDING SUMMARY
No studies describing the use of succimer during lactation have been located. The molecular weight (about 182) suggests that the drug will be excreted into milk. The effects of this exposure on a nursing infant are unknown. However, because the use of succimer implies poisoning with lead, or other heavy metals, these substances might also be excreted into milk and cause toxicity in a nursing infant. Therefore, breastfeeding is contraindicated in women receiving succimer.
References
1.Domingo JL. Developmental toxicity of metal chelating agents. Reprod Toxicol 1998;12:499–510.
2.Product information. Chemet. Sanofi-Synthelabo, 2002.
3.Domingo JL, Ortega A, Paternain JL, Llobet JM. Oral meso-2,3-dimercaptosuccinic acid in pregnant Sprague-Dawley rats: teratogenicity and alterations in mineral metabolism. I. Teratological evaluation. J Toxicol Environ Health 1990;30:181–90.
4.Paternain JL, Ortega A, Domingo JL, Llobet JM. Oral meso-2, 3-dimercaptosuccinic acid in pregnant Sprague-Dawley rats: teratogenicity and alterations in mineral metabolism. II. Effect on mineral metabolism. J Toxicol Environ Health 1990;30:191–7.
5.Domingo JL, Paternain JL, Llobet JM, Corbella J. Developmental toxicity of subcutaneously administered meso-2,3-dimercaptosuccinic acid in mice. Fundam Appl Toxicol 1988;11:715–22.
6.Domingo JL, Bosque MA, Corbella J. Effects of oral meso-2, 3-dimercaptosucinic acid (DMSA) administration on late gestation and postnatal development in the mouse. Life Sci 1990;47:1745–50.
7.Taubeneck MW, Domingo JL, Llobet JM, Keen CL. Meso-2, 3-dimercaptosuccinic acid (DMSA) affects maternal and fetal copper metabolism in Swiss mice. Toxicology 1992;72:27–40.
8.Domingo JL, Bosque MA, Piera V. meso-2,3-dimercaptosuccinic acid and prevention of arsenite embryotoxicity and teratogenicity in the mouse. Fundam Appl Toxicol 1991;17:314–20.
9.Bosque MA, Domingo JL, Llobet JM, Corbella J. Effects of Meso-2, 3-dimercaptosuccinic acid (DMSA) on the teratogenicity of sodium arsenate in mice. Bull Environ Contam Toxicol 1991;47:682–8.
10.Hughes JA, Sparber SB. Reduction of methylmercury concentration in neonatal rat brains after administration of dimercaptosuccinic acid to dams while pregnant. Res Commun Chem Pathol Pharmacol 1978;22:357–63.
11.Sanchez DJ, Gomez M, Llobet JM, Domingo JL. Effects of meso-2,3-dimercaptosuccinic acid (DMSA) on methyl mercury-induced teratogenesis in mice. Ecotoxicol Environ Saf 1993;26:33–9.
12.Chen S, Golemboski KA, Sander FS, Dietert RR. Persistent effect of in utero meso-2,3-dimercaptosuccinic acid (DMSA) on immune function and lead-induced immunotoxicity. Toxicology 1999;132:67–79.
13.Horowitz BZ, Mirkin DB. Lead poisoning and chelation in a mother–neonate pair. J Toxicol Clin Toxicol 2001;39:727–31.
14.Shannon M. Severe lead poisoning in pregnancy. Ambul Pediatr 2003;3:37–9.