Anti-infective
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Several studies have described the use of amoxicillin and potassium clavulanate for various infections in pregnant women. Most studies have observed no adverse effects in the fetus or newborn attributable to the combination (see Amoxicillin and Ticarcillin). However, one study did report an association with necrotizing enterocolitis (NEC) in newborns.
FETAL RISK SUMMARY
Clavulanic acid is a β-lactamase inhibitor produced by Streptomyces clavuligerus that is combined, as the potassium salt, with the penicillin antibiotics, amoxicillin or ticarcillin, to broaden their antibacterial spectrum of activity. No adverse fetal effects were observed in mice, rats, and pigs administered potassium clavulanate in combination with amoxicillin or ticarcillin during gestation (1–5).
Following a single oral dose of amoxicillin (250 mg) and potassium clavulanate (125 mg) in humans, both agents crossed the placenta to the fetus (6,7). Cord blood levels were found 1 hour after the dose, with peak levels occurring at 2–3 hours. In one study, the mean peak maternal serum and umbilical cord blood levels occurred at 2 hours with values of 2.20 and 1.23 mcg/mL, respectively (fetal:maternal ratio 0.56) (7). Both amoxicillin and potassium clavulanate have been demonstrated in the amniotic fluid (6–8), with peak concentrations of clavulanate (0.44 mcg/mL) measured 5.5 hours after administration (7). A study using in vitro perfused human placentas demonstrated the transfer of potassium clavulanate when concentrations on the maternal side were 10–13 mcg/mL, but not at 2–6 mcg/mL (8). A fetal/maternal gradient of 1:1 was obtained at the higher concentrations.
In addition to the above, several studies have described the use of amoxicillin–clavulanic acid (ACA) for various infections in pregnant women either without causing fetal or newborn harm (9–11) or causing newborn harm (12).
A 2001 randomized study (ORACLE 1) was conducted in patients with preterm, prelabor rupture of fetal membranes to determine neonatal health benefits of three antibiotic regimens (12). The regimens, compared with a placebo group (N = 1225) were erythromycin (250 mg) (N = 1197), amoxicillin (250 mg)–clavulanic acid (125 mg) (N = 1212), or both (N = 1192) four times daily for 10 days or until delivery. The primary outcome measures were specific outcomes or a composite of neonatal death, chronic lung disease, or major cerebral abnormality. For these neonatal outcomes, the two groups with ACA had no benefit over placebo, whereas erythromycin use resulted in significantly better outcomes (both composite and specific). When any-ACA exposure was compared with no-ACA for outcomes with suspected or proven NEC, the results were 92 (3.8%) and 58 (2.4%) (p = 0.004). The authors thought that a possible mechanism for this outcome was that the ACA combination selected for Clostridium difficile and that abnormal colonization of the neonatal intestinal tract was one possible mechanism for NEC (12).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 556 newborns had been exposed to clavulanic acid (presumably in combination with penicillins) during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 24 (4.3%) major birth defects were observed (24 expected). Specific data were available for six defect categories, including (observed/expected) 5/6 cardiovascular defects, 2/1 oral clefts, 1/2 polydactyly, 0/1 limb-reduction defects, 1/1 hypospadias, and 2/0.3 spina bifida. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother’s disease, concurrent drug use, and chance, may be involved.
In a 1997 prospective, double-blind, randomized, controlled study, two antibiotic regimens (ampicillin–sulbactam for 72 hours followed by amoxicillin–clavulanate or ampicillin for 72 hours followed by amoxicillin) were effective for prophylaxis in women with preterm premature rupture of the membranes who had received antenatal corticosteroids alone (13). Although both combinations reduced the frequency of neonatal mortality, sepsis, and respiratory distress syndrome and increased birth weight compared with corticosteroids alone, statistical significance was reached only with the ampicillin–sulbactam/amoxicillin–clavulanate combination (26.3% vs. 48.6%; p ≤ 0.05).
In a 2004 study, 191 women treated with amoxicillin– clavulanic acid (subjects) in the 1st trimester were matched with 191 controls exposed to amoxicillin only (14). Maternal age, birth weight, gestational age at birth, and rates of live births and abortions were comparable between the two groups. The rates of major malformations in subjects (3/158, 1.9%) and controls (5/163, 3%) (p = 0.49; relative risk 0.62, 95% confidence interval 0.15–2.55) were within the expected baseline risk for the general population (14).
BREASTFEEDING SUMMARY
Both amoxicillin and ticarcillin are excreted into breast milk (see Amoxicillin and Ticarcillin), but data pertaining to potassium clavulanate have not been located. Excretion probably occurs because of the low molecular weight (about 237). The effects of the β-lactamase inhibitor on the nursing infant are unknown.
References
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