Animal studies have revealed evidence of fetal harm; embryonic deaths and malformations of anophthalmia and microphthalmia have been observed in the offspring of pregnant rats who were administered large doses of chloroquine. This drug crosses the placenta. There are no controlled data in human pregnancy; however, a moderate amount of data on pregnant women (between 300 and 1000 pregnancy outcomes), including prospective studies in long-term use with large exposure, have not shown a significant increase in risk of congenital malformations or poor pregnancy outcomes.

Therapeutic doses of 4-aminoquinolines have been associated with central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal hemorrhages, and abnormal retinal pigmentation.

According to the US CDC, this drug is a recommended agent for the treatment of chloroquine-sensitive malaria species during pregnancy; it is also recommended as an alternative for malaria prophylaxis during pregnancy for women traveling to areas where chloroquine-resistant Plasmodium falciparum has not been reported.

Malaria in pregnant women increases the risk for adverse pregnancy outcomes, including prematurity, spontaneous abortion, and stillbirth. Travel to malarious areas should be avoided during pregnancy; if this is not possible, women should receive effective prophylaxis.

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: D
US FDA pregnancy category: Not formally assigned to a pregnancy category.

See references

In 1 study, daily drug exposures to infants from breast milk were estimated to be less than 2% of the maternal dose (after adjusting for body weight).

Infants exposed to this drug during breastfeeding receive only small amounts of the drug. In infants up to at least 1 year of age, careful follow-up found no adverse effects on growth, vision, or hearing.

This drug is usually available as the sulfate salt with hydroxychloroquine constituting about 75% of the labeled dose of hydroxychloroquine sulfate. This drug has a half-life of over 1 month. Some studies have not been clear regarding salt form and dose of the products used and others have sampled milk after only a few doses before steady state was reached, making interpretation of some of the data difficult.

In a patient starting therapy with 200 mg (salt unspecified) twice a day, the highest milk level detected was 10.6 mcg/L from 3 to 12 hours after the fourth dose. After the first 48 hours of therapy with a total dosage of 800 mg, a total of 3.2 mcg was excreted into her breast milk, amounting to 0.0003% of the mother's total dosage; however, it is unlikely that steady state had been reached at this time.

A woman who had been breastfeeding for 9 months began taking 400 mg (as sulfate equivalent to 310 mg base) nightly; after 6 weeks of this regimen, steady-state milk levels were 1.46, 1.09, and 1.09, at 2, 9.5, and 14 hours after 1 dose, respectively, and 0.85 mg/L at 17.7 hours after a dose on the following day. According to author estimation, the infant would receive 0.11 mg/kg/day or about 2% of the mother's weight-adjusted dose. No adverse effects were reported in her 9-month-old breastfed infant.

After taking 200 mg (probably sulfate equivalent to 150 mg base) once or twice a day (report was unclear) before and during pregnancy, 2 women had milk levels measured after delivery; drug levels were 344 and 1424 mcg/L at unspecified times after dosing. According to author estimation, the 2 infants would receive 0.06 and 0.2 mg/kg/day. These authors also reported 2 other women with milk drug levels of 1131 and 1392 mcg/L at unreported times after unspecified doses (presumably 200 to 400 mg/day); according to author estimation, their 2 infants would receive no more than 0.2 mg/kg/day via breast milk.

Numerous milk samples were collected from 6 women using 400 mg (n=5) or 200 mg (n=1) per day; the milk level averaged 376 mcg/L (range: 20 to 1463 mcg/L) as parent drug and 36 mcg/L (range; 11 to 111 mcg/L) as desethylchloroquine. According to author estimation, a fully breastfed infant would receive 1 mg of parent drug and 0.066 mg of desethylchloroquine per day.

At 7 time points between 0 and 18 hours after dosing, 13 women who were on long-term therapy donated milk samples. Milk drug levels averaged 416 mcg/L in 1 woman taking 100 mg/day, 358 to 746 mcg/L in 3 women taking 100 mg twice a day, 672 to 980 mcg/L in 4 women taking 200 mg once a day, and 1336 to 3269 mcg/L in 5 women taking 200 mg twice a day.

Milk drug levels were determined at 5 times over a 12-hour period just before and after dosing in 33 women who had been taking this drug for at least 1 year and were exclusively breastfeeding; samples were collected at a median of 4 weeks postpartum (range: 1 to 16 weeks postpartum). Doses (as sulfate) ranged from 200 mg once every 2 days to 200 mg twice a day, with most taking 200 mg once (24%) or twice (64%) a day; these doses are equivalent to 155 and 310 mg base. Peak milk level was reached 2 to 4 hours after dosing. Average milk levels were dose related and ranged from 0.4 to 1.2 mg/L (mean: 0.7 mg/L) with 200 mg once a day and 0.5 to 3.7 mg/L (mean: 1.4 mg/L) with 200 mg twice a day. The estimated infant dose averaged 0.2 mg/kg/day with maternal doses of 400 mg/day and 0.1 mg/kg/day with lower maternal doses; these corresponded to weight-adjusted infant doses of 1.9% to 3.2% of the maternal dose. A relative infant dose of 9.8% was found in 1 woman taking 200 mg twice a day; she was instructed to discontinue breastfeeding. No ocular toxicity or growth abnormalities were found at 1-year follow-up of the infants.

After 5 mothers took 200 mg/day during pregnancy and breastfeeding (1 for 30 months), flash electroretinograms performed on the infants were normal.

A group of investigators have reported numerous infants whose mother took this drug during pregnancy and were breastfed during maternal use. An abstract reported 16 infants breastfed for 1 to 19 months and followed up at an average of 24 months (range: 1 to 86 months) with no evidence of visual or hearing deficits. In a letter, they reported 8 breastfed infants followed up at 1, 6, and 12 months of age who had normal growth and development and who had thorough, normal eye examinations at 1 and 12 months of age. In a case series, 13 mothers taking 200 mg/day (as sulfate) breastfed their infants for an average of 2.8 months (range: 1 to 6 months); no infant had evidence of retinal, motor, or growth abnormalities during 12 months of follow-up. The authors concluded that the benefits of breastfeeding outweighed the risk of this drug. It appears the 8 infants reported in the letter were included among the 13 infants in the case series, but it is unclear whether the 16 infants reported in the abstract were part of the case series.

Caution is recommended; benefit to mother should outweigh risk to the infant.
-According to some experts: Use is considered acceptable.

Excreted into human milk: Yes (small amounts)

Comments:
-Infants are extremely sensitive to the toxic effects of 4-aminoquinolines.
-When used for malaria prophylaxis, the amount in breast milk is too small to cause harmful effects in the nursing infant but is insufficient to confer any benefit on the infant; the breastfed infant will require separate chemoprophylaxis.
-Very limited data available regarding the safety in breastfed infants during long-term maternal therapy.

See references