Animal studies have revealed evidence of teratogenicity. In rats administered oral doses 2.5 times the human dose for toxoplasmosis therapy, a significant increase in abnormalities (e.g., cleft palate, brachygnathia, oligodactyly, microphthalmia) was observed; this drug also produced terata (e.g., meningocele in hamsters, cleft palate in miniature pigs) when given in oral doses 5 times the human dose for toxoplasmosis therapy. There are no controlled data in human pregnancy.

From the 28th week of gestation until birth, 1 woman was treated with 25 to 50 mg/day for central nervous system toxoplasmosis. No adverse fetal reactions occurred.

Another woman taking this drug weekly (with chloroquine and dapsone) at the time of conception and for 45 days thereafter gave birth to a stillborn infant with a severe defect of the abdominal and thoracic wall and a missing left arm.

According to the Panel on Opportunistic Infections in Adults and Adolescents with HIV, recommended uses during pregnancy are treatment and secondary prophylaxis of toxoplasmic encephalitis and alternate treatment of Pneumocystis pneumonia. This drug should not be used in the first trimester due to teratogenicity concerns.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.
-According to some authorities: This drug should not be used during the first trimester of pregnancy (contraindicated).
-According to some authorities: Use is not recommended during the first trimester of pregnancy unless the benefit outweighs the risk.

AU TGA pregnancy category: B3
US FDA pregnancy category: C

Comments:
-The risks associated with using this drug must be weighed against the dangers of abortion or fetal malformation due to the infection.
-According to some authorities: Treatment with this drug and sulfadiazine during pregnancy is indicated if placental/fetal infection confirmed or mother is at risk of serious sequelae; however, this combination therapy should be restricted to the second and third trimesters.
-Females of childbearing potential should be warned to avoid becoming pregnant during therapy.
-Because this drug is a folate antagonist, it should be given with leucovorin (calcium folinate/folinic acid) supplementation if used during pregnancy.

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LactMed, WHO: Use is considered acceptable.
-According to some experts: Caution is recommended.
-According to some authorities: Breastfeeding is not recommended during use of this drug (contraindicated).
-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

Comments:
-This drug has been used without apparent harmful effects in the nursing infant.
-WHO: The infant should not receive any other anti-folate agent.
-This drug is considered compatible with breastfeeding by the American Academy of Pediatrics.

It has been estimated that over 9 days an average weight infant would receive about 45% of the maternal dose.

In 3 women treated with a combination of dapsone and this drug, the milk:serum ratio of this drug ranged from 0.46 to 0.66. It has been reported that after a single 75 mg dose, about 3 to 4 mg of the drug was estimated to pass on to the feeding child over 48 hours.

Drug milk levels were reported after doses of 25, 50, or 75 mg in 16 women; milk levels ranged from 2.7 to 3.3 mg/L at 6 hours after dosing, 1.6 to 2 mg/L at 24 hours after dosing, and 0.66 to 1 mg/L at 48 hours after dosing (3 women only). Reported milk levels were not dose-proportional in this old study using an antiquated assay method.

A single 12.5 mg oral dose was given to 3 women 2 to 5 days postpartum; milk samples were collected periodically for about 9 days after dosing. Assuming an intake of 1 L/day of milk, the infants would receive 0.14, 0.21, and 0.34 mg in milk over the study period; according to author calculation, these values compared to an average of 30% (range: 16.8% to 45.6%) of the maternal weight-adjusted dose.

Administration of this drug to mothers of 26 primarily breastfed infants (2 to 6 months old) who were infected with malaria was curative in the infants. The regimen consisted of 75 mg followed 4 to 7 days later by a 50 to 75 mg dose. Efficacy appeared related to breastfeeding habits, as infants in another tribal group who breastfed their infants less extensively were not protected.

A case report showed that a mother received a single 75 mg oral dose followed by 25 mg/week which cured malaria in her breastfed infant and protected her infant against malaria infection for 6 months. After the mother missed her dose for 2 weeks, the infant developed symptoms of malaria. No side effects were reported in any of the infants.

See references