AZITHROMYCIN

Fetal Risk Summary

Azithromycin, an azalide antibiotic that is categorized as a member of the macrolides, is derived from erythromycin. Animal studies using mice and rats treated with doses up to maternal toxic levels (i.e., 200 mg/kg/day) revealed no impairment of fertility or harm to the fetus (1).

Azithromycin crosses the human placenta at term (2,3). In 20 women scheduled for elective cesarean section, a single 1-g oral dose of azithromycin was given 6 (N=2), 12 (N=7), 24 (N=5), 72 (N=5), or 168 (N=1) hours before delivery. The mean maternal concentrations at delivery for the five groups were 311, 144, 63, 60, and <10 ng/mL, respectively, where as the corresponding mean cord serum levels were 19, 26, 27, 19, and <10 ng/mL, respectively. Cerebrospinal fluid levels in the mothers (all had spinal anesthesia) were undetectable (<16 ng/mL) in each group.

In an ex vivo experiment with term human placentas utilizing a single placental cotyledon model, the mean transplacental transfer of three macrolide antibiotics (azithromycin, erythromycin, and roxithromycin) were 2.6%, 3.0%, and 4.3%, respectively (3). The percentages were calculated as the ratio between the steady state level in fetal venous and maternal arterial sides (3).

A number of reports have described the use of azithromycin in human pregnancy, but in only one of the studies (10) was the drug used early in gestation (4,5,6,7,8,9 and 10). A 1994 abstract reported that 16 pregnant patients with cervicitis caused by chlamydia had been treated with a single 1-g oral dose of the antibiotic in a comparison trial with erythromycin (4). Fifteen of the women had negative tests for chlamydia after treatment. No data were given on gestational age at the time of treatment or on the pregnancy outcomes. In a second, similar report, also comparing efficacy with erythromycin, 15 pregnant women with chlamydial cervicitis were treated with a single 1-g oral dose (5). All of the women had negative cervical swabs for chlamydia as analyzed by direct DNA assay 14 days after the dose. Three more recent reports have also documented the efficacy of azithromycin in the treatment of pregnant women with chlamydia (6,7 and 8). Of the five reports, only the last study (8) indicated the gestational age at treatment (about 24 weeks'), but none provided information on fetal outcome. In contrast to the effectiveness of azithromycin for chlamydia infections, a single 1-g oral dose of the antibiotic was ineffective in reducing lower genital colonization with ureaplasma in pregnant women between 22 and 34 weeks' gestation with ruptured membranes or preterm labor (9).

A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (10). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Azithromycin was taken during the 1st trimester in 11 pregnancies. The outcomes of these pregnancies were 1 elective abortion and 10 normal, term babies (10).

Although no congenital malformations were observed in the above study, the data are too limited to assess the safety of azithromycin. Moreover, the study lacked sensitivity to identify minor anomalies because of the absence of standardized examinations. Late appearing major defects may also have been missed due to the timing of the questionnaires. However, macrolide antibiotics are not considered to be major human teratogens.

Breast Feeding Summary

Azithromycin accumulates in breast milk (11). A woman, in the 1st week after a term vaginal delivery, was treated with a single 1-g oral dose of azithromycin for a wound infection following a bilateral tubal ligation and then, because of worsening symptoms, given 48 hours of IV gentamicin and clindamycin. She was discharged from the hospital on a 5-day course of azithromycin, 500 mg daily, but only took three doses because she wanted to resume breast feeding that had been stopped during azithromycin therapy. The patient continued pumping her breasts during this time to maintain milk flow and resumed breast feeding 24 hours after the third dose of the antibiotic. Drug doses and approximate time from the first dose were 1 g (0 hours), 500 mg (59 hours), 500 mg (83 hours), and 500 mg (107 hours). Milk concentrations of azithromycin and times from the first dose were 0.64 µg/mL (48 hours), 1.3 µg/mL (60 hours), and 2.8 µg/mL (137 hours) (maternal serum concentrations were not determined). The authors attributed the antibioticís milk accumulation to its lipid solubility and ion trapping of a weak base.

References

1. Product information. Zithromax. Pfizer Labs, 1994.
2. Ramsey PS, Vaules MB, Vasdev G, Andrews WW, Ramin KD. Maternal and transplacental pharmacokinetics of azithromycin (abstract). Am J Obstet Gynecol 2000;182:S98.
3. Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. Br J Obstet Gynaecol 2000;107:770–5.
4. Edwards M, Rainwater K, Carter S, Williamson F, Newman R. Comparison of azithromycin and erythromycin for Chlamydia cervicitis in pregnancy (abstract). Am J Obstet Gynecol 1994;170:419.
5. Bush MR, Rosa C. Azithromycin and erythromycin in the treatment of cervical chlamydial infection during pregnancy. Obstet Gynecol 1994;84:61–3.
6. Rosenn M, Macones GA, Silverman N. A randomized trial of erythromycin and azithromycin for the treatment of chlamydia infection in pregnancy (abstract). Am J Obstet Gynecol 1996;174:410.
7. Wehbeh H, Ruggiero R, Ali Y, Lopez G, Shahem S, Zarou D. A randomized clinical trial of a single dose of zithromycin in the treatment of chlamydia among pregnant women (abstract). Am J Obstet Gynecol 1996;174:361.
8. Wehbeh HA, Ruggeirio RM, Shahem S, Lopez G, Ali Y. Single-dose azithromycin for chlamydia in pregnant women. J Reprod Med 1998;43:509–14.
9. Ogasawara KK, Goodwin TM. Efficacy of azithromycin in reducing lower genital ureaplasma colonization in women at risk for preterm delivery (abstract). Am J Obstet Gynecol 1997;176:S57.
10. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105: 882–9.
11. Kelsey JJ, Moser LR, Jennings JC, Munger MA. Presence of azithromycin breast milk concentrations: a case report. Am J Obstet Gynecol 1994;170:1375–6.