HYDROXYCHLOROQUINE

Fetal Risk Summary

Hydroxychloroquine is used for the treatment of malaria, discoid and systemic lupus erythematosus (SLE), and rheumatoid arthritis. A 1988 review described several References relating to animal studies with the closely related agent, chloroquine (1). In pregnant mice, rats, rabbits, and monkeys, chloroquine crosses the placenta to the fetus (1). In fetal mice and monkeys, the drug accumulates for long intervals, up to 5 months in mice, in the melanin structures of the eyes and inner ears (1,2). Teratogenicity studies with chloroquine using monkeys have not been published. However, in rats, only high doses were teratogenic, producing skeletal and ocular defects (1). In pregnant mice, chloroquine alone was not teratogenic, but in combination with radiation, a significant increase in cleft palates and tail anomalies was observed (1). No similar data are available for hydroxychloroquine.

Published data relating to the use of hydroxychloroquine during human pregnancy are scarce but do not indicate that the drug poses a significant risk to the fetus. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 2 of which had 1st trimester exposure to hydroxychloroquine (3). Neither child had a congenital malformation. A 1974 Reference reported no abnormalities in a fetus after a therapeutic abortion at 14 weeks' gestation (4). The fetus had been exposed to the antimalarial agent, 200 mg twice daily, since the time of conception. Examination of the temporal bones, the embryonal precartilage, the anlages of the auditory ossicles, and the membranous labyrinth demonstrated a normal 14-week stage of development, indicating an apparent lack of drug-induced ototoxicity in this fetus (4). A short 1983 communication described the use of 200 mg/day of hydroxychloroquine during the first 16 weeks of gestation for the treatment of maternal discoid lupus erythematosus (5). A male infant was eventually delivered who was alive and well at 2 years of age.

The use of hydroxychloroquine during 27 pregnancies in 23 women with mild to moderate SLE was described in a 1995 abstract (6). In 17 of the pregnancies, the drug was used at a dose of 200–400 mg daily throughout gestation. The outcomes of these cases included 2 miscarriages, 2 perinatal deaths, 1 infant with congenital heart block (in a Ro-positive mother), and 12 normal newborns. In 6 other pregnancies, hydroxychloroquine was started after conception, three during the 1st trimester. In the remaining four cases, therapy was stopped after diagnosis of pregnancy, resulting in a worsening of the disease and higher doses of prednisolone, and pregnancy termination in 1 because of severe renal lupus. No fetal or newborn adverse effects related to hydroxychloroquine were observed. A follow-up of 20 newborns for at least 3 years found that all were healthy. The authors concluded that hydroxychloroquine was safe in pregnancy, and because of the risk of lupus flare, discontinuing therapy during pregnancy represented a greater danger to the fetus (6).

Other investigators have reached similar conclusions as to the safety of hydroxychloroquine in the treatment of SLE during pregnancy (7,8). These authors described nine pregnancies (plus seven from an earlier paper) in which hydroxychloroquine (200 mg/day) was used throughout gestation without producing congenital malformations. In the present series of nine pregnancies, five newborns were delivered preterm and four at term. Long-term follow-up of the children exposed in utero has been normal. Because of the very long elimination half-life of the drug from maternal tissues (weeks to months), the authors concluded that discontinuing the drug when pregnancy was known would not eliminate fetal exposure, but could jeopardize the pregnancy from a lupus flare (7,8).

The use of hydroxychloroquine as an antimalarial, instead of chloroquine, has been recommended because of the belief that hydroxychloroquine is less toxic (1). However, little data are available to substantiate this practice, either in terms of congenital malformations or in optic or otic toxicity. From published reports of fetal exposure to either chloroquine or hydroxychloroquine, one source cited an incidence of 7 infants with congenital anomalies from 188 live births, a rate of 4.5% (1). This value is within the expected 3%–6% incidence of congenital malformations in a nonexposed population.

In summary, hydroxychloroquine does not seem to pose a significant risk to the fetus, especially with lower doses. No reports of retinal or ototoxicity after in utero exposure have been located. The Centers for Disease Control stated that hydroxychloroquine may be used during pregnancy for antimalarial prophylaxis since, in prophylactic doses, the agent has not been shown to be harmful to the fetus (9, 10). The adult antimalarial prophylactic dose is 400 mg/week (2). The use of higher doses for prolonged periods, such as those used for SLE, acute attacks of malaria, and rheumatoid arthritis probably represents an increased fetal risk, but the magnitude of this increase is unknown. At least one source has recommended that the use of hydroxychloroquine for rheumatoid arthritis or SLE be avoided during pregnancy (1), but recent reports (6,7 and 8) do not support this conclusion. Moreover, stopping therapy when a pregnancy became known would not, as discussed above, stop exposure of the embryo and fetus to the drug, but could increase the risk because of a lupus flare.

Breast Feeding Summary

Two reports have described the excretion of small amounts of hydroxychloroquine into breast milk. A 27-year-old woman was treated with hydroxychloroquine, 400 mg (310 mg base) each night, for an exacerbation of lupus erythematosus (11). She had been breast-feeding her infant for 9 months. No mention of the infant's condition or of the presence of toxic effects was made by the authors of this report. Milk samples were collected 2.0, 9.5, and 14.0 hours after one dose and 17.7 hours after a second dose. Milk concentrations of hydroxychloroquine base at the four times were 1.46, 1.09, 1.09, and 0.85 µg/mL, respectively. A maternal blood sample was collected 15.5 hours after the first dose. Hydroxychloroquine base concentrations in whole blood and plasma were 1.76 and 0.20 µg/mL, respectively. The authors estimated that the infant was consuming, based on 1000 mL of milk, a daily dose of 1.1 mg hydroxychloroquine base, or approximately 0.35% of the mother's daily dose (11).

Much lower milk concentrations of drug were obtained from a 28-year-old woman who was being treated with hydroxychloroquine, 200 mg twice daily, for rheumatoid arthritis (12). Treatment had been stopped for 6 months during pregnancy and then restarted 2 months later because of arthritis relapse. A total of 3.2 µg of the drug was recovered from her milk over a 48-hour interval, representing 0.0005% of the mother's dose. The highest milk concentration of the agent, 10.6 ng/mL, was found in the 39–48 hour sample. It was not stated whether the infant was allowed to breast-feed.

Because of the slow elimination rate and the potential for accumulation of a toxic amount in the infant, breast feeding during daily therapy with hydroxychloroquine should be undertaken cautiously (11,12 and 13). The administration of once-weekly doses, such as those used for malaria prophylaxis, would markedly reduce the amount of drug available to the nursing infant and, consequently, produce a much lower risk of accumulation and toxicity. Although breast feeding during maternal malarial prophylaxis is not thought to be harmful, the amount of hydroxychloroquine in milk is insufficient to provide protection against malaria in the infant (10). The American Academy of Pediatrics classifies the drug as compatible with breast feeding (14).

References

1. Roubenoff R, Hoyt J, Petri M, Hochberg MC, Hellmann DB. Effects of antiinflammatory and immunosuppressive drugs on pregnancy and fertility. Semin Arthr Rheum 1988;18:88–110.
2. Product information. Plaquenil. Sanofi Winthrop Pharmaceuticals, 1997.
3. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:299.
4. Ross JB, Garatsos S. Absence of choroquine-induced ototoxicity in a fetus. Arch Dermatol 1974;109:573.
5. Suhonen R. Hydroxychloroquine administration in pregnancy. Arch Dermatol 1983;119:185–6.
6. Buchanan NMM, Toubi E, Khamashta MA, Lima F, Kerslake S, Hughes GRV. The safety of hydroxychloroquine in lupus pregnancy: experience in 27 pregnancies (abstract). Br J Rheumatol 1995;34(Suppl 1):14.
7. Parke AL, Rothfield NF. Antimalarial drugs in pregnancy—the North American experience. Lupus 1996;5(Suppl 1):567–9.
8. Parke A, West B. Hydroxychloroquine in pregnant patients with systemic lupus erythematosus. J Rheumatol 1996;23:1715–8.
9. Centers for Disease Control. Adverse reactions and contraindications to antimalarials. MMWR 1988;37:282–3.
10. Centers for Disease Control. Recommendations for the prevention of malaria among travelers. MMWR 1990;39:1–10.
11. Nation RL, Hackett LP, Dusci LJ, Ilett KF. Excretion of hydroxychloroquine in human milk. Br J Clin Pharmacol 1984;17:368–9.
12. Ostensen M, Brown ND, Chiang PK, Aarbakke J. Hydroxychloroquine in human breast milk. Eur J Clin Pharmacol 1985;28:357.
13. Anderson PO. Drug use during breast-feeding. Clin Pharm 1991;10:594–624.
14. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.