Antidote
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Only two reports of human pregnancy experience with edetate, both involving a short course in late gestation, have been located. Moreover, interpretation of the rat study is hindered by the presumed oral administration of edetate, a drug that is poorly absorbed from the gastrointestinal (GI) tract. That study did suggest, however, that the observed fetal malformations were induced by zinc deficiency. The human cases and limited animal data are insufficient to assess the risk for the human embryo and fetus. Dietary zinc supplementation might be an option if prolonged treatment with edetate calcium disodium was required during pregnancy, but this has not been studied. In addition, hypotension is a reported adverse effect in adults, and in a pregnant patient, this could jeopardize placental perfusion and the fetus. However, lead is a well-known reproductive toxicant that has significant associations with preterm birth, reduced birth weight and postnatal growth, minor congenital anomalies, and deficits in postnatal neurological or neurobehavioral status (1). Therefore, if indicated, the maternal, and possibly the embryo–fetal, benefit of therapy appear to outweigh any unknown direct or indirect risks (2).
FETAL RISK SUMMARY
The chelating agent edetate calcium disodium (edetate) is the calcium chelate of disodium ethylenediaminetetraacetate. It is indicated for the reduction of blood levels and depot stores of lead in acute or chronic lead poisoning and lead encephalopathy. Edetate also forms stable chelates with other divalent or trivalent metals that can displace calcium, such as cadmium, iron, manganese, mercury, and zinc, but not copper. However, insignificant amounts of iron and manganese are chelated, and mercury is either too tightly bound to be chelated or is stored in inaccessible body compartments. In contrast, the excretion of zinc is significantly increased. Edetate must be given by injection (IM preferred but also by IV) because it is poorly absorbed from the GI tract. The drug is not metabolized and is excreted by the kidneys with an elimination half-life of 20–60 minutes (3).
Reproduction studies have been conducted in pregnant rats. In one study, doses up to 13 times the human dose (presumed to be based on body weight) revealed no evidence of impaired fertility or fetal harm. In a second study, doses up to about 25–40 times the human dose caused fetal malformations, but the anomalies were prevented by simultaneous supplementation of dietary zinc (3).
A 1998 review summarized the developmental toxicity of metal chelating agents, including ethylenediaminetetraacetic acid (EDTA) and its salts (disodium, trisodium, calcium disodium, and tetrasodium edetate) (4). The author cited several animal studies showing teratogenicity that was proven to be secondary to EDTA-induced zinc deficiency. Different incidences of teratogenicity were observed depending on the route of administration (IV, SC, gavage, or diet) and dose. In one study, oral administration of EDTA and its salts, even at maternally toxic doses, had little or no teratogenic effects in rats. The different outcomes were thought to be partially due to poor absorption of the compounds after oral administration (4).
It is not known if edetate crosses the human placenta to the embryo or fetus. The molecular weight (about 374) is low enough for transfer to the fetus. In addition, small amounts of the drug cross the blood–brain barrier as about 5% of the plasma concentration can be found in spinal fluid. However, the very short elimination half-life will limit the amount of drug at the maternal–fetal interface.
The first known case of lead poisoning treated with edetate in a pregnant woman was reported in 1964 (5). A family of six (father, mother, and four male siblings) was diagnosed with lead poisoning caused by using battery cases as fuel in the living room stove for several months. The mother, who was 8 months pregnant, had a blood lead level of 0.24 mg/dL. She was treated with a 7-day course of edetate (75 mg/kg/day). Four weeks later, she delivered an apparently healthy 3.2-kg male infant. The cord blood lead level was undetectable (<0.06 mg/dL). At follow-up, the physical and neurologic examination and developmental assessment were normal at 4.25 years (5).
An unusual case of lead poisoning in a 17-year-old pregnant woman was apparently reported by two different groups of authors from the same New York hospital (6,7). The patient had eaten paint from the walls of her apartment for several months during pregnancy. She was hospitalized at about 38 weeks’ gestation because of abdominal pain, paresthesias in her feet, and calf pain. A blood sample yielded a lead level of 86 mcg/mL, whereas the amniotic fluid lead level was 90 mcg/mL. She was treated with IV edetate 1 g twice daily for 3 days. Two days after chelation therapy, her blood level was 41 mcg/mL. Six days later, she delivered a 2665-g female infant spontaneously. The cord blood lead concentration was 60 mcg/mL, whereas the maternal level at discharge was 26 mcg/mL. The small-for-date infant’s head circumference was 32 cm (10th percentile), and the length was 45 cm (25th percentile). Radiographs revealed a dense skull with delayed deciduous dental development and abnormal long bones. At about 2 years of age, the girl’s growth and development were normal (6,7).
A 2002 report described the use of IV edetate (dose not specified) and IM dimercaprol in a woman at 30 weeks’ gestation with a high blood lead concentration (5.2 μmol/L; goal ≤0.48 μmol/L) (8). Twenty-four hours after initiation of chelation therapy, her lead level was 2.3 μmol/L. Twelve hours later, labor was induced because of uterine hemorrhage, and she gave birth to a 1.6-kg (75th percentile) female infant. Lead concentration in the cord blood was 7.6 μmol/L. The Apgar scores were 4 and 6 (presumably at 1 and 5 minutes, respectively). The newborn was flaccid with absent reflexes, no movement to noxious stimuli, and no gag reflex, but she did have spontaneous eye movement. Bilateral diaphragmatic palsy was confirmed by fluoroscopy. During her 7 months of hospitalization, the infant received multiple courses of chelation to treat the intrauterine lead intoxication. In spite of this therapy, she had right sensorineural deafness and neurodevelopment delay at discharge. Oral succimer was continued at home because the blood lead level was still elevated (0.95 μmol/L). The mother’s lead source was identified as herbal tablets that had been prescribed for a GI complaint. She had taken the tablets periodically over the last 9 years and throughout pregnancy. Mercury also was present in some of the tablets. The lead intake during pregnancy was estimated to be 50 times the average weekly intake of Western populations (8).
In a 2003 report, four women with severe lead poisoning were treated with IV edetate during the 3rd trimester, including one also treated with dimercaprol. 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 (9).
BREASTFEEDING SUMMARY
No reports describing the use of edetate calcium disodium (edetate) during lactation have been located. The molecular weight (about 374) suggests that the drug will be excreted into breast milk, but the very short elimination half-life will limit the amount excreted. Moreover, edetate is poorly absorbed after oral dosing, at least from the adult GI tract. The risk to a nursing infant from exposure to the drug in milk is unknown but appears to be very low or nonexistent. However, because the use of edetate implies poisoning with lead, this metal also will be excreted into milk and is toxic to a nursing infant. Therefore, breastfeeding is contraindicated in women receiving edetate.
References
1.Schardein JL. Metals. Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:879.
2.Bailey B. Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? Birth Def Res (Part A) 2003;67:133–40.
3.Product information. Calcium Disodium Versenate. Eli Lilly and Company, 2004.
4.Domingo JL. Developmental toxicity of metal chelating agents. Reprod Toxicol 1998;12:499–510.
5.Angle CR, McIntire MS. Lead poisoning during pregnancy. Fetal tolerance of calcium disodium edetate. Am J Dis Child 1964;108:436–9.
6.Timpo AE, Amin JS, Casalino MB, Yuceoglu AM. Congenital lead intoxication. J Pediatr 1979;94:765–7.
7.Pearl M, Boxi LM. Radiographic findings in congenital lead poisoning. Radiology 1980;136:83–4.
8.Tait PA, Vora A, James S, Fitzgerald DJ, Pester BA. Severe congenital lead poisoning in a preterm infant due to a herbal remedy. Med J Aust 2002;177:193–5.
9.Shannon M. Severe lead poisoning in pregnancy. Ambul Pediatr 2003;3:37–9.