Animal studies have revealed evidence of embryofetal toxicity; embryofetal developmental toxicity was observed at dose about 3 to 16 times the maximum recommended therapeutic dose based on body surface area comparison. This drug crosses the placenta to the fetus with fetal levels similar to those in the mother. There are no controlled data in human pregnancy; however, observational studies as well as a meta-analysis (including a small number of prospective studies with exposure to this drug during pregnancy) have shown no increase in rate of birth defects or spontaneous abortions at recommended doses for prophylaxis and treatment of malaria.

When administered to women at high doses throughout pregnancy, fetal abnormalities (including visual loss, ototoxicity, cochlear-vestibular dysfunction) have been reported.

According to the US CDC, this drug is the drug of choice for the treatment of chloroquine-sensitive malaria species during pregnancy; it is also the drug of choice 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 of maternal death, miscarriage, stillbirth, and low birth weight with associated risk of neonatal death. 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.

AU TGA pregnancy category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

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

AU TGA pregnancy category:
-Malaria treatment: D
-Malaria prophylaxis: A
US FDA pregnancy category: Not formally assigned to a pregnancy category.

See references

LactMed: When used once a week, this drug has been used without apparent harmful effects; since no information available on daily use while nursing, an alternative agent may be preferred, particularly while breastfeeding newborn or preterm infant.
WHO: Use is considered acceptable; infants should be monitored for side effects (hemolysis, jaundice), particularly if premature of younger than 1 month.
-According to some authorities: This drug has been used for malaria prophylaxis without apparent harmful effects; breastfeeding is not recommended during use of this drug for rheumatoid disease (long-term high doses).
-According to some authorities: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Excreted into human milk: Yes (small amounts)

Comments:
-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.
-WHO: Use should be avoided in glucose-6-phosphate dehydrogenase deficient infants.
-This drug is considered compatible with breastfeeding by the American Academy of Pediatrics.

This drug has a serum half-life of over 1 month. Some studies have sampled milk after only a few doses before steady state was reached, making interpretation of some of the data difficult. The active metabolite, desethylchloroquine, has been measured in only a few studies.

The excretion of this drug and its major metabolite, desethylchloroquine, in breast milk was studied in 11 lactating mothers after a single 600 mg (base) oral dose. The maximum daily dose of the drug that the infant could receive from breastfeeding was about 0.7% of the maternal start dose of the drug in malaria chemotherapy; therefore, separate chemoprophylaxis is required for the infant.

Milk drug levels were measured in 1 mother after an oral regimen of 600 mg (base)/day for 2 days, followed by 300 mg/day for 3 days. Milk levels averaged 1.2 mg/L (range: 0.2 to 2.8 mg/L) in 17 random samples during, and 4 days after dosing; metabolite levels averaged 0.68 mg/L (range: 0.1 to 1.5 mg/L).

In 9 women given a total dose of 25 mg/kg (base) over 3 days (10, 10, and 5 mg/kg) for malaria treatment, up to 8 breast milk samples were collected over the subsequent 28 days. This drug was still detectable in milk 28 days after the last dose.

At 2 to 5 days postpartum, 3 women were given a single 600 mg (base) oral dose. Milk samples were collected periodically for about 9 days after dosing and AUC values were calculated; milk levels were not reported. Assuming a daily intake of 1 L of milk, authors calculated the 3 infants would receive 0.4, 0.58, and 0.76 mg in milk over the study period; these values averaged 3.1% of the maternal weight-adjusted dose.

At 17 days postpartum, 6 women were given a single 5 mg/kg (phosphate) IM dose. Milk drug levels averaged 227 mg/L (range: 192 to 319 mg/L) 2 hours after dosing; no further milk levels were obtained.

At 2 to 2.5 months postpartum, 6 women were given a single 300 mg (base) oral dose. Peak drug level in milk averaged 3.97 mg/L at 3 hours after dosing; elimination half-life from milk averaged 132 hours. According to author estimation, an exclusively breastfed infant would receive 0.55% of the total maternal dose (not weight adjusted) in 24 hours.

After 600 mg (base) orally in 11 women, peak chloroquine plus desethylchloroquine in milk averaged 4.4 mg/L occurred at 14.4 hours (average) after dosing; this drug and its active metabolite were detected in the urine of the 4 infants who were tested. According to author estimation (using peak milk level), an exclusively breastfed infant would receive up to 14% of the maternal weight-adjusted dose. Elimination half-life from milk averaged 8.8 days.

In 10 women taking 300 mg/week orally during pregnancy then 100 mg/day for the last 10 days of pregnancy and first 10 days postpartum, milk samples were collected daily for 3 days during the first 10 days postpartum at the end of nursing (time after dosing not provided); median whole milk level was 352 mcg/L. Milk was separated into cell-rich and cell-poor fractions; cell-rich fraction had a median drug level of 746 mcg/L and colostrum cells had a calculated level of 81 mg/L. The authors hypothesized that the high drug level in milk cells might protect the infants against HIV transmission.

The excretion of this drug and its active metabolite into breast milk was measured in 16 women administered 750 mg (phosphate [equal to 465 mg base]) daily for 3 consecutive days starting on the day of delivery for malaria prophylaxis. Foremilk and hindmilk samples were collected on postpartum days 3, 4, 5, 10, and 18 to 22; levels of this drug and its active metabolite varied widely among patients, with milk levels averaging 226 mcg/L (range: 44 to 336 mcg/L) and 97 mcg/L (range: 26 to 175 mcg/L), respectively. The infant doses for this drug and its active metabolite averaged 34 mcg/kg/day (range: 7 to 50 mcg/kg/day) and 97 mcg/kg/day (range: 26 to 175 mcg/kg/day), respectively, which would be too low to provide effective malaria prophylaxis for the breastfed infant. An exclusively breastfed infant would receive average maternal weight-adjusted doses of 2.3% and 1% of this drug and its active metabolite, respectively.

Several authors have indicated that malaria prophylaxis in nursing mothers with this drug is common in endemic areas. At this time, no reports of side effects in breastfed infants have been published.

The very small amounts of antimalarial drugs transferred in breast milk are insufficient to provide adequate protection against malaria. If prophylaxis is required, infants should receive recommended doses of antimalarial drugs. Current guidelines should be consulted for additional information.

See references