Antimalarial/Amebicide
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Although some studies have suggested a low risk of congenital malformations, the lack of a pattern in the defects suggests that a causative association is unlikely. In any event, the maternal and fetal benefit of preventing and treating malaria far outweighs the risk, if any, to the embryo–fetus.
FETAL RISK SUMMARY
Chloroquine is the drug of choice for the prophylaxis and treatment of sensitive malaria species during pregnancy (1–4). The drug is also indicated for the treatment of extraintestinal invasion by the protozoan parasite, Entamoeba histolytica (5). Chloroquine is generally considered safe for these purposes by most authorities (1–7). However, the antimalarial is embryotoxic and teratogenic in rats given a 1000-mg/kg dose, causing embryonic death in 27% and producing anophthalmia and microphthalmia in 47% of the surviving fetuses (8).
Chloroquine crosses the placenta to the fetus, with fetal concentrations approximating those in the mother (9). In seven mothers at term in the second stage of labor, chloroquine, 5 mg/kg IM, produced mean levels in maternal blood, cord venous blood, and cord arterial blood that were all about 0.7 mcg/mL. The time interval from administration to sampling averaged 5.3 hours (range 2.4–10.5 hours). In a pregnant monkey, an 125I-labeled chloroquine analog crossed the placenta and concentrated in the fetal adrenal cortex and retina (10). Chloroquine rapidly crosses the placenta in pregnant mice and selectively accumulates in the melanin structures of the fetal eyes (11). The drug was retained in the ocular structures for 5 months after elimination from the rest of the body.
The risks of complications from malarial infection occurring during pregnancy are increased, especially in women not living in endemic areas (i.e., nonimmune women) (12–14). Infection is associated with a number of severe maternal and fetal outcomes: anemia, abortion, stillbirths, prematurity, low birth weight, fetal distress, and congenital malaria (12–14). However, it is not yet clear if all of these are related to malarial infection (13). For example, prevention of low birth weight and the resulting risk of infant mortality by antimalarial chemoprophylaxis has not yet been proven (13). Increased maternal morbidity and mortality includes adult respiratory distress syndrome, massive hemolysis, disseminated intravascular coagulation, acute renal failure, and hypoglycemia, with the latter symptom occurring in up to 50% of women in whom quinine is used (14). Severe Plasmodium falciparum malaria in pregnant nonimmune women has a poor prognosis and may be associated with asymptomatic uterine contractions, intrauterine growth restriction, fetal tachycardia, fetal distress, hypoglycemia, and placental insufficiency because of intense parasitization (13). Because of the severity of this disease in pregnancy, chemoprophylaxis is recommended for women of childbearing age traveling in areas where malaria is present (12–14).
Congenital malaria may occur in up to 10% of infants born to mothers not living in endemic areas (14). In most cases, clinical malaria manifests 3–8 weeks after birth, probably as a result of exchange of infected maternal erythrocytes at birth, and is characterized by fever, hepatosplenomegaly, jaundice, and thrombocytopenia (14). In areas of hyperendemicity, transplacental passage of maternal IgG may protect the newborn against development of clinical malaria (14).
Congenital defects have been reported in three infants delivered from one mother who was treated during pregnancy with 250–500 mg/day of chloroquine for discoid lupus erythematosus (15). In addition, this woman also had two normal infants, who had not been exposed to chloroquine during gestation, and one normal infant who had been exposed. Anomalies in the three infants were Wilms’ tumor at age 4 years, left-sided hemihypertrophy (one infant), and cochleovestibular paresis (two infants).
A 1985 report summarized the results of 169 infants exposed in utero to 300 mg of chloroquine base once weekly throughout pregnancy (16). The control group consisted of 454 nonexposed infants. Two infants (1.2%) in the study group had anomalies (tetralogy of Fallot and congenital hypothyroidism) compared with four control infants who had defects (0.9%). Based on these data, the authors concluded that chloroquine is not a major teratogen, but a small increase in birth defects could not be excluded (16).
BREASTFEEDING SUMMARY
Chloroquine is excreted into breast milk (9,17). When chloroquine, 5 mg/kg IM, was administered to six nursing mothers 17 days postpartum, mean milk and serum concentrations 2 hours later were 0.227 mcg/mL (range 0.163–0.319 mcg/mL) and 0.648 mcg/mL (range 0.46–0.95 mcg/mL), respectively. The mean milk:blood ratio was 0.358 (range 0.268–0.462). Based on an average consumption of 500 mL of milk/day, an infant would have received about 114 mcg/day of chloroquine, an amount considered safe by the investigators (9). In an earlier study, three women were given a single dose of 600 mg of chloroquine 2–5 days postpartum (17). Serum and milk samples were collected up to 227 hours after administration. The milk:plasma ratios (AUC) for chloroquine and the principal metabolite, desethylchloroquine, ranged from 1.96 to 4.26 and from 0.54 to 3.89, respectively. Based on a daily milk intake of 1000 mL, the nursing infants would have ingested between 2.2% and 4.2% of the maternal doses over a 9-day period (17).
Although the amounts of chloroquine excreted into milk are not considered to be harmful to a nursing infant, they are insufficient to provide adequate protection against malaria (12). The American Academy of Pediatrics classifies chloroquine as compatible with breastfeeding (18).
References
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10.Dencker L, Lindquist NG, Ulberg S. Distribution of an I-125 labeled chloroquine analogue in a pregnant Macaca monkey. Toxicology 1975;5:255–64. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989;140–1.
11.Product information. Aralen. Sanofi Pharmaceuticals, 2000.
12.CDC. Recommendations for the prevention of malaria among travelers. MMWR 1990;39:1–10.
13.World Health Organization. Practical chemotherapy of malaria. WHO Tech Rep Ser 1990;805:1–141.
14.Subramanian D, Moise KJ Jr, White AC Jr. Imported malaria in pregnancy: report of four cases and review of management. Clin Infect Dis 1992;15:408–13.
15.Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryngol 1964;80:407–12.
16.Wolfe MS, Cordero JF. Safety of chloroquine in chemosuppression of malaria during pregnancy. Br Med J 1985;290:1466–7.
17.Edstein MD, Veenendaal JR, Newman K, Hyslop R. Excretion of chloroquine, dapsone and pyrimethamine in human milk. Br J Clin Pharmacol 1986;22:733–5.
18.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.