CEFTRIAXONE

Fetal Risk Summary

Ceftriaxone is a parenteral, semisynthetic cephalosporin antibiotic. Reproduction studies in rats found no evidence of impaired fertility or reproduction performance at a dose approximately 20 times the recommended human dose or, in mice, rats, and nonhuman primates, of embryotoxicity, fetotoxicity, or teratogenicity at doses approximately 20, 20, and 3 times, respectively, the recommended human dose (1).

A 1993 report described the pharmacokinetics of cetriaxone, 2 g IV once daily for about 10 days, in nine women at 28 to 40 weeks' gestation who were being treated for chorioamnionitis or pyelonephritis (2). No accumulation of the antibiotic was noted and the pharmacokinetic profile was similar to healthy, nonpregnant adults. No adverse effects in fetuses or newborns were observed.

Peak levels in cord blood following 1- or 2-g IV doses occurred at 4 hours with concentrations varying between 19.6 and 40.6 µg/mL (1–8 hours) (3,4 and 5). Amniotic fluid levels over 24 hours ranged from 2.2 to 23.4 µg/mL with peak levels occurring at 6 hours (3,4 and 5). Ceftriaxone concentrations in the first voided newborn urine were highly variable, ranging from 6 to 92 µg/mL. Elimination half-lives from cord blood (7 hours), amniotic fluid (6.8 hours), and placenta (5.4 hours) were nearly identical to maternal serum (3,4,6). No adverse effects in the newborns were mentioned.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 60 newborns had been exposed to ceftriaxone during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Four (6.7%) major birth defects were observed (three expected), including three cardiovascular defects (one expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. A possible association between ceftriaxone and cardiovascular defects is suggested, but other factors, such as the mother's disease, concurrent drug use, and chance, may be involved. However, other cephalosporin antibiotics from this study have shown possible associations with congenital malformations (see also Cefaclor, Cephalexin, and Cephradine).

Cephalosporins are usually considered safe to use during pregnancy. Ceftriaxone, 1 g IV daily, has been used in the treatment of pyelonephritis occurring in the second half of pregnancy (7). No adverse fetal outcomes attributable to the drug were observed.

Ceftriaxone 1 g IV has been used for preoperative prophylaxis prior to emergency cesarean section (8). Amniotic fluid and fetal serum levels ranged from 0.016 to 0.25 µg/mL (mean 0.085 µg/mL) and from 0.66 to 18.4 µg/mL (mean 4.6 µg/mL), respectively.

Gonorrhea infecting 114 pregnant women in the 2nd trimester was treated with a single 250-mg IM dose of ceftriaxone in a study published in 1993 (9). The treatment was compared with approximately similar numbers of pregnant women treated with spectinomycin or amoxicillin with probenecid. Ceftriaxone and spectinomycin were similar in efficacy and both were superior to the amoxicillin/probenecid regimen. A 20-year-old woman with endocarditis due to Neisseria sicca was treated for 4 weeks with ceftriaxone, 2 g IV every 12 hours, late in the 3rd trimester (10). She eventually delivered a term, small-for-gestational-age female infant, whose low weight was attributed to the mother's chronic disease state.

Breast Feeding Summary

Ceftriaxone is excreted into breast milk in low concentrations. Following either 1- or 2-g IV or IM doses, peak levels of 0.5–0.7 µg/mL occurred at 5 hours, approximately 3%–4% of maternal serum (3,4). High protein binding in maternal serum probably limited transfer to the milk (3,4). The antibiotic was still detectable in milk at 24 hours (3). Elimination half-lives after IV and IM doses were 12.8 and 17.3 hours, respectively (3). Chronic dosing would eventually produce calculated steady-state levels in 1.5–3 days in the 3- to 4-µg/mL range (4). Although these levels are low, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required. The American Academy of Pediatrics considers the drug to be compatible with breast feeding (11).

References

1. Product information. Rocephin. Roche Laboratories, 1997.
2. Bourget P, Fernandez H, Quinquis V, Delouis C. Pharmacokinetics and protein binding of ceftriaxone during pregnancy. Antimicrob Agents Chemother 1993;37:54–9.
3. Kafetzis DA, Brater DC, Fanourgakis JE, Voyatzis J, Georgakopoulos P. Placental and breast-milk transfer of ceftriaxone (C). In Proceedings of the 22nd Intersci Conf on Antimicrob Ag Chemother, Miami, Florida, October 4–6, 1982:155. New York:Academic Press, 1983.
4. Kafetzis DA, Brater DC, Fanourgakis JE, Voyatzis J, Georgakopoulos P. Ceftriaxone distribution between maternal blood and fetal blood and tissues at parturition and between blood and milk postpartum. Antimicrob Agents Chemother 1983;23:870–3.
5. Cho N, Kunii K, Fukunago K, Komoriyama Y. Antimicrobial activity, pharmacokinetics and clinical studies of ceftriaxone in obstetrics and gynecology. In Proceedings of the 13th Inter Cong Chemother, Vienna, Austria, August 28 to September 2, 1983:100/64–66. Princeton:Excerpta Medica, 1984.
6. Graber H, Magyar T. Pharmacokinetics of ceftriaxone in pregnancy. Am J Med 1984;77:117–8.
7. Sanchez-Ramos L, McAlpine KJ, Adair CD, Kaunitz AM, Delke I, Briones DK. Pyelonephritis in pregnancy: once-a-day ceftriaxone versus multiple doses of cefazolin. Am J Obstet Gynecol 1995;172:129–33.
8. Lang R, Shalit I, Segal J, Arbel Y, Markov S, Hass H, Fejgin M. Maternal and fetal and tissue levels of ceftriaxone following preoperative prophylaxis in emergency cesarean section. Chemotherapy 1993;39:77–81.
9. Cavenee MR, Farris JR, Spalding TR, Barnes DL, Castaneda YS, Wendel GD Jr. Treatment of gonorrhea in pregnancy. Obstet Gynecol 1993;81:33–8.
10. Deger R, Ludmir J. Neisseria sicca endocarditis complicating pregnancy. A case report. J Reprod Med 1992;37:473–5.
11. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.