Animal studies have failed to reveal evidence of teratogenicity, fetotoxicity, or other fetal harm; reproduction studies in rats, rabbits, and mice at doses similar to maximum recommended daily dose (based on body surface area comparisons) showed no evidence of fetal harm. This drug crosses the placenta and rapidly enters fetal circulation. Published data include more than 5000 pregnant women who used this drug during pregnancy (many during the first trimester); 1 study showed increased risk of cleft lip (with or without cleft palate) in infants exposed in utero, but these findings were not confirmed. More than 10 studies enrolled more than 5000 pregnant women to assess antibiotic use (including this drug) for bacterial vaginosis on incidence of preterm delivery; most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes after exposure to this drug during pregnancy. No increased risk was observed in 3 studies assessing the risk of infant cancer after exposure to this drug during pregnancy; however, these studies had limited ability to detect such a signal. There are no controlled data in human pregnancy.

AU TGA pregnancy category B2: 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 are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Trichomoniasis:
-According to some authorities: Use is contraindicated during the first trimester of pregnancy.
-According to some authorities: Use is not recommended during the first trimester of pregnancy; use in the second and third trimesters should be reserved for those in whom local palliative treatment has been inadequate to control symptoms.
-According to some authorities: Use is not recommended unless considered essential by physician; in such cases, short high-dose regimens are not recommended.

All Other Indications:
-According to some authorities: Use is not recommended during the first trimester of pregnancy.
-According to some authorities:
---IV therapy: Use is not recommended unless clearly needed.
---Oral therapy: Use is not recommended unless considered essential by physician; in such cases, short high-dose regimens are not recommended.
-According to some authorities: This drug should be used during pregnancy only if the benefit outweighs the risk.

AU TGA pregnancy category: B2
US FDA pregnancy category: Not assigned.

Risk summary: No controlled data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-According to the US CDC, symptomatic women, at any stage of pregnancy, should be tested and considered for treatment of trichomoniasis.

See references

With maternal IV and oral therapy, breastfed infants receive this drug in doses less than those used to treat infections in infants, although the active metabolite adds to the total infant exposure; drug and metabolite plasma levels are measurable, but less than maternal plasma levels. Cases of candidal infections and diarrhea have been reported; a comparative trial suggested oral and rectal colonization with Candida might be more common in infants exposed to this drug.

Genotoxicity and mutagenicity in bacteria, carcinogenicity in animals, and possible mutagenicity in human have given rise to concern about exposure of healthy infants to this drug via breast milk. The relevance of such findings has been questioned; no definitive study has been performed in humans.

A single 200 mg oral dose was given to 10 women at 5 days postpartum. Milk levels averaged 3.4, 2.8, and 1.3 mg/L at 4, 8, and 12 hours after the dose, respectively; the 12-hour level was averaged from 5 women. After the maternal dose, the 5-day-old infants (n=10) were breastfed every 4 hours. At 8 hours after the dose, 2 infants had serum drug levels of 0.28 and 0.4 mg/L and levels were unmeasurable (less than 0.05 mg/L) in 3 infants; at 12 hours after the dose, another 2 infants had serum drug levels of 0.2 mg/L and levels were unmeasurable in another 3 infants. No signs of oral or gastrointestinal upset were observed in the 10 infants during the 12-hour study period.

In a randomized study, 17 mothers received 200 mg orally 3 times a day for 7 days postpartum; milk drug levels (collected on day 6; times not provided) averaged 4.7 mg/L (range: 1.1 to 15.2 mg/L).

A single 2 g oral dose was given to 3 women for trichomoniasis. Milk levels averaged 45.8, 27.9, 19.1, 12.6, and 3.5 mg/L at 2, 8, 12, 18, and 36 hours after the dose, respectively; the 18-hour and 36-hour levels were averaged from 2 women. According to author estimation, infants would receive 25.3 mg (total) over the 48 hours after the dose.

At 0 to 22 days postpartum, 11 women received 200 mg orally 3 times a day and 4 women received 400 mg orally 3 times a day for postpartum endometritis. Single milk samples collected after 1 to 9 days of therapy and from 30 minutes to 4 hours after a 200 mg dose had 1.6 to 12.2 mg/L of unchanged drug and 1.1 to 3.8 mg/L of hydroxymetronidazole; milk samples collected 2 to 3 hours after a 400 mg dose had 11.6 to 18 mg/L of unchanged drug and 2.4 to 6.3 mg/L of hydroxymetronidazole. Blood samples were collected from their breastfed newborn infants 1 to 2 hours after maternal dosing. In 11 infants whose mothers were taking 600 mg/day, plasma drug levels and hydroxymetronidazole levels averaged 0.8 mg/L (range: 0.3 to 1.4 mg/L) and 0.4 mg/L (range: 0.1 to 0.8 mg/L), respectively; in 4 infants whose mothers were taking 1200 mg/day, plasma drug levels and hydroxymetronidazole levels averaged 2.4 mg/L (range: 0.6 to 4.9 mg/L) and 1.1 mg/L (range: 0.4 to 2.3 mg/L), respectively. Blood samples were collected from their breastfed newborn infants 1 to 2 hours after maternal dosing. In 11 infants whose mothers were taking 600 mg/day, plasma drug levels and hydroxymetronidazole levels averaged 0.8 mg/L (range: 0.3 to 1.4 mg/L) and 0.4 mg/L (range: 0.1 to 0.8 mg/L), respectively; in 4 infants whose mothers were taking 1200 mg/day, plasma drug levels and hydroxymetronidazole levels averaged 2.4 mg/L (range: 0.6 to 4.9 mg/L) and 1.1 mg/L (range: 0.4 to 2.3 mg/L), respectively. The infants had plasma drug levels and plasma hydroxymetronidazole levels ranging from 4% to 32% and 8% to 96% of maternal plasma levels, respectively. No observable side effects occurred in the 16 newborn breastfed infants (aged 0 to 22 days) during the 9 days of the study.

On days 3 and 4 postpartum, milk samples were collected from 12 women taking 400 mg orally 3 times a day at an average of 4.3 days postpartum; 7 of their breastfed infants had serum levels measured 4 to 8 hours after maternal dosing and 30 to 90 minutes after breastfeeding. Milk levels of unchanged drug averaged 15.5, 12.9, 10.6, and 9.1 mg/L at 2, 4, 6, and 8 hours after dosing, respectively; milk levels of hydroxymetronidazole averaged 5.5, 5.7, 5.6, and 5.5 mg/L at 2, 4, 6, and 8 hours after dosing, respectively. According to author estimation, a breastfed neonate ingesting 500 mL milk/day with this maternal dose would receive less than 10% of the recommended newborn dose of this drug. Infant plasma levels averaged 1.6 mg/L for unchanged drug and 1.4 mg/L for hydroxymetronidazole; these levels corresponded to 12.5% and 25.6% of maternal plasma levels for unchanged drug and hydroxymetronidazole, respectively.

At 1 month postpartum, a single 500 mg IV dose was administered to 15 women; breast milk levels averaged 7.55 mg/L at 2 hours after dosing.

After a cesarean section, 3 postpartum women received 500 mg IV 3 times a day for 2 days. A breast milk sample was collected from the women 1 to 2 hours after dosing on the second day of therapy; milk drug levels were 7.3, 9.6, and 10.1 mg/L.

A case of diarrhea and secondary lactose intolerance was possibly due the infant receiving this drug via breast milk in the early neonatal period.

In a controlled comparative study, 35 newborn infants were monitored for 10 days during maternal therapy with this drug and another antibiotic (33 ampicillin, 1 erythromycin, and 1 cephalexin) for postpartum infection/prophylaxis; doses and administration routes were not provided, but some mothers received the drugs IV initially and then were switched to oral therapy. Compared to infants of mothers who used ampicillin alone or no antibiotics, more infants exposed to this drug and ampicillin had very loose stools than in the other groups, especially when administered IV. More frequent and heavier growth of Candida species was observed in the oral and perianal swabs of infants exposed to this drug, but statistical significance was not reached. Oral thrush developed in 1 infant exposed to this drug and ampicillin. No differences observed between the groups in diaper rash, feeding problems, or weight gain to time of discharge.

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
-According to some authorities: Breastfeeding is not recommended during use of this drug.
-According to some authorities: Use is not recommended unless considered essential by physician.

Excreted into human milk: Yes

Comments:
-This drug is secreted in breast milk in concentrations similar to those found in the plasma.
-Due to the potential for tumorigenicity in animal studies, a nursing mother may choose to pump and discard her milk during therapy and for 24 hours after therapy ends and feed her infant stored human milk or formula.
-Some sources recommend discontinuing breastfeeding for 12 to 24 hours after single-dose maternal treatment; opinions vary among experts whether use is advisable during longer-term therapy while breastfeeding.

See references