Antibiotic
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
The human pregnancy data do not suggest an embryo–fetal risk of developmental toxicity from azithromycin. The antibiotic has not been associated with an increased risk of pyloric stenosis.
FETAL RISK SUMMARY
Azithromycin, an azalide antibiotic, is derived from erythromycin. It is in the macrolide anti-infective class that includes clarithromycin and erythromycin.
Animal studies using rats and mice treated with daily doses up to maternal toxic levels revealed no impairment of fertility or harm to the fetus. These daily doses were about 1 and 0.5 times, respectively, the human dose of 2 g/day based on BSA (HD) (1).
Long-term studies for carcinogenic effects have not been conducted, but tests for mutagenic and clastogenic effects were negative. No evidence of impaired fertility was found in rats given daily doses up to about 0.05 times the HD (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, whereas 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 (4–22) have described the use of azithromycin in human pregnancy. 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 (6–8). 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). Two women with scrub typhus (tsutsugamushi disease) in the 2nd trimester were treated successfully with 3-day courses of azithromycin (10). Both delivered healthy infants.
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed ≥1 of 34 newly marketed drugs by general practitioners in England (11). Data were obtained by questionnaires sent to the prescribing physicians 1 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 (11).
In a 2005 abstract, 145 pregnant women were exposed to a new macrolide (38 azithromycin, 53 clarithromycin, and 54 roxithromycin), of which 103 were exposed in the 1st trimester (12). The rates of congenital anomalies compared with 928 exposed to a nonteratogen were similar (4.0% vs. 3.75%, p = 0.156). In a 2006 study, comparisons were made between three groups each containing 123 pregnancies: azithromycin (88 exposed in 1st trimester), nonteratogenic antibiotics, and nonteratogenic agents (13). The rates of congenital anomalies were not significantly different, 3.4%, 2.3%, and 3.4%, respectively. The authors concluded that azithromycin was relatively safe during pregnancy (13).
A retrospective cohort study using data from Tennessee Medicaid included 30,049 infants born in 1985–2000 was published in 2009 (14). Infants with fetal exposures in the 1st trimester to four antibiotics recommended for potential bioterrorism attacks (azithromycin, amoxicillin, ciprofloxacin, and doxycycline) were compared with infants with no fetal exposure to any antibiotic. Erythromycin was included as a positive control. In the 559 infants exposed to azithromycin and no other antibiotics, the number of cases, risk ratios, and 95% CI were as follows: any malformation (23, 1.37, 0.85–2.22), cardiac (7, 1.13, 0.50–2.55), musculoskeletal (8, 1.58, 0.61–4.10), genitourinary (4, 1.34, 0.44–4.03), gastrointestinal (4, 1.57, 0.52–4.75), CNS (1, 0.81–6.27), and orofacial (2, 4.85, 0.88–26.60). The authors concluded that the four antibiotics should not result in a greater incidence of overall major malformations (see also Amoxicillin, Ciprofloxacin, and Doxycycline) (14).
A 2009 case report described the use of azithromycin (500 mg/day for 6 days) for the treatment of Q fever in the 9th week of pregnancy (15). A healthy 3500-g infant was born at 40 weeks’.
A study evaluating the effects of mass treatment (cefixime, azithromycin, and metronidazole) for AIDS prevention in Uganda was published in 1999 (16). Compared with controls, the prevalences of trichomoniasis, bacterial vaginosis, gonorrhea, and Chlamydia infection were significantly lower, but no difference was observed in the incidence of HIV infection. A second study using this same group of patients found, in addition to the lower rates of infection, reduced rates of neonatal death, low birth weight, and preterm delivery (17). However, in a third study involving the same Uganda women as above, children of 94 women with Trichomonas vaginalis who had been treated during pregnancy with the three-drug combination had increased low birth weight (<2500 g) and preterm birth rate compared with untreated controls (18). The authors concluded that treatment of the condition during pregnancy was harmful and that it was most likely due to metronidazole.
A prospective multicenter study published in 2008 compared pregnant women exposed to a new macrolide (azithromycin, clarithromycin, or roxithromycin) with two comparison groups (19). Of 161 women exposed to a macrolide, 118 were exposed in the 1st trimester. The rate of major malformations in the study group was 4.1% compared with 2.1% of those exposed to other antibiotics (OR = 1.41, 95% CI 0.47–4.23). The authors concluded that the use of the new macrolides did not represent an increased risk of congenital defects strong enough for an elective abortion (19).
A prospective, multicenter observational 2012 study was conducted by teratogen information services in Italy, Israel, Czech Republic, the Netherlands, and Germany (20). Of the 608 women exposed to macrolides, 511 were exposed in the 1st trimester. The study group was compared with 773 women exposed to nonteratogens in the 1st trimester. The rate of major congenital defects were similar in the groups (3.4% vs. 2.4%, p = 0.36; OR 1.42, 95% CI 0.70–2.88) or in the rate of cardiovascular defects (1.6% vs. 0.9%). The rates for azithromycin (N = 134) were 5.2% vs. 2.4% (p = 0.09; OR 2.23, 95% CI 0.91–5.5) and 3% vs. 0.9% (p = 0.06; OR 3.59, 95% CI 0.99–12.88) (20).
Two reports, one an abstract, have examined the potential of azithromycin in the prevention of premature birth (21,22). In the abstract, azithromycin combined with metronidazole was compared with placebo in three different periods: <32 weeks’, <35 weeks’, and <37 weeks’ (21). The combination did not decrease the incidence of preterm birth. In the other report, azithromycin was compared with placebo. The results provided no evidence that the use of the antibiotic could prevent preterm birth (22).
In a 2003 Danish study, 188 women received a macrolide (see Breastfeeding Summary) within 30 days of birth and none of their infants had infantile hypertrophic pyloric stenosis (23).
BREASTFEEDING SUMMARY
Azithromycin accumulates in breast milk. 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, was given 48 hours of IV gentamicin and clindamycin (24). 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 breastfeeding that had been stopped during azithromycin therapy. The patient continued pumping her breasts during this time to maintain milk flow and resumed breastfeeding 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 mcg/mL (48 hours), 1.3 mcg/mL (60 hours), and 2.8 mcg/mL (137 hours) (maternal serum concentrations were not determined). The authors attributed the antibiotic’s milk accumulation to its lipid solubility and ion trapping of a weak base (24).
A 2003 study investigated the association between maternal use of macrolides and infantile hypertrophic pyloric stenosis (23). The Danish population-based cohort study comprised 1166 women who had been a prescribed macrolide (azithromycin, clarithromycin, erythromycin, spiramycin, or roxithromycin) from birth to 90 days postnatally compared with up to 41,778 controls. The odds ratios (ORs) for stenosis were 2.3–3.0, depending on the postnatal period of exposure (42, 56, 70, or 90 days), but none were significant. When stratified by gender, the ORs for males were 1.8–3.1 and again were not statistically significant. For females, the ORs at 70 and 90 days post-birth were 10.3 and 7.5, respectively, but only the former was significant (95% CI 1.2–92.3) (23).
Investigators from Israel examined the possible association between macrolide (azithromycin, clarithromycin, erythromycin, or roxithromycin) exposure in milk and infantile hypertrophic pyloric stenosis in a 2009 study (25). They compared 55 infants exposed to a macrolide antibiotic with 36 infants exposed to amoxicillin. In the macrolide group, seven (12.7%) had an adverse reaction (rash, diarrhea, loss of appetite, or somnolence), whereas three infants (8.3%) in the amoxicillin group had an adverse reaction (rashes or somnolence). The rates of adverse reactions were comparable. No cases of infantile hypertrophic pyloric stenosis were observed (25).
References
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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.
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7.Wehbeh H, Ruggiero R, Ali Y, Lopez G, Shahem S, Zarou D. A randomized clinical trial of a single dose of azithromycin in the treatment of chlamydia among pregnant women (abstract). Am J Obstet Gynecol 1996;174:361.
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17.Gray RH, Wabwire-Mangen F, Kigozi G, Sewankambo NK, Serwadda D, Moulton LH, Quinn TC, O’Brien KL, Meehan M, Abramowsky C, Robb M, Wawer MJ. Randomized trial of presumptive sexually transmitted disease therapy during pregnancy in Rakai, Uganda. Am J Obstet Gynecol 2001;185:1209–17.
18.Kigozi GG, Brahmbhatt H, Wabwire-Mangen F, Wawer MJ, Serwadda D, Sewankambo N, Gray RH. Treatment of Trichomonas in pregnancy and adverse outcomes of pregnancy: a subanalysis of a randomized trial in Rakai, Uganda. Am J Obstet Gynecol 2003;189:1398–400.
19.Bar-Oz B, Diav-Citrin O, Shechtman S, Tellem R, Arnon J, Francetic I, Berkovitch M, Ornoy A. Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study. Eur J Obstet Gynecol Reprod Biol 2008;141:31–4.
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21.Hauth JC, Cliver S. Hodgkins P, Andrews WW, Schwebke JR, Hook EW, Goldenberg RL. Mid-trimester metronidazole and azithromycin did not prevent preterm birth in women at increased risk: a double-blind trial. Am J Obstet Gynecol 2001;185(6 Suppl):S86.
22.van den Broek NR, White SA, Goodall M, Ntonya C, Kayira E, Kafulafula G, Neilson JP. The APPLe study: a randomized, community-based, placebo-controlled trial of azithromycin for the prevention of preterm birth, with meta analysis. PloS Med 2009;6:e100091.
23.Sorensen HT, Skriver MV, Pedersen L, Larsen H, Ebbesen F, Schonheyder HC. Risk of infantile hypertrophic pyloric stenosis after maternal postnatal use of macrolides. Scand J Infect Dis 2003;35:104–6.
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25.Goldstein LH, Berlin M, Tsur L, Bortnik O, Binyamini L, Berkovitch M. The safety of macrolides during lactation. Breastfeed Med 2009;4:157–200.