| TERIS Summary |
| TERIS Agent Number: | 2856 | Bibliographic Search Date: | 05/2020 |
| Agent Name: | AZITHROMYCIN |
| Azithromycin is a macrolide antibiotic that is administered orally for the treatment of bacterial or chlamydial infections. |
Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation: |
NONE TO MINIMAL |
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Quality and Quantity of Data on Which Risk Estimate is Based: |
FAIR TO GOOD |
Comments: |
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Summary of Teratology Studies: MAJOR CONGENITAL ANOMALIES
Epidemiological studies of the effects of antibiotic use during pregnancy may be subject to confounding by indication because antibiotics are prescribed to treat infections that are often accompanied by fever, which itself may increase the risk of congenital anomalies in the child (Dreier et al., 2014). To avoid this bias, the infants of women who were treated with penicillin, which is thought not to increase the risk of fetal damage (PLEASE SEE AGENT SUMMARY ON PENICILLIN FOR MORE INFORMATION), rather than the infants of unexposed mothers, are often used as a comparator in such studies.
The risk of major congenital anomalies was not increased among the infants of 5037 women treated with azithromycin during the first trimester of pregnancy when compared to infants whose mothers were treated with a penicillin during pregnancy in a Danish record-linkage study (Damkier et al., 2019).
The frequency of major congenital anomalies was not significantly increased among the infants of 883 women who received prescriptions for azithromycin during the first trimester of pregnancy in comparison to the infants of women who were not treated with antibiotics early in pregnancy in a Quebec cohort study (Muanda et al., 2017a). However, a weak association with major congenital anomalies was observed with maternal azithromycin treatment early in pregnancy when the comparison was to the infants of women who received prescriptions for penicillin during the first trimester (odds ratio=1.25, 95% confidence interval 1.01-1.53) (Muanda et al., 2017a). No association with any of 12 anatomic classes or subclasses of malformations was seen in either comparison. The reported rate of major malformations identified in the first year of life in this study was surprisingly high (9.8% among infants of unexposed pregnancies), raising concern about misclassification of birth defect status in many cases.
The frequency of major congenital anomalies was no greater than expected among 559 infants of women who filled prescriptions for azithromycin during the first four lunar months of pregnancy or among the infants of 1459 women who filled prescriptions for azithromycin anytime during pregnancy in a record linkage study of Tennessee Medicaid data (Cooper et al., 2009). No association was found with major congenital anomalies of the orofacial, cardiovascular, musculoskeletal, genitourinary, gastrointestinal, or central nervous systems in either time period in this study.
The frequency of major malformations was not significantly increased among 151 infants born to women treated with azithromycin monotherapy during the first trimester of pregnancy when compared to infants whose mothers were treated with a penicillin antibiotic during the first trimester in a population-based study of health records from the United Kingdom’s Clinical Practice Research Datalink (Fan et al., 2020).
The frequency of congenital anomalies was not significantly increased among 134 liveborn infants whose mothers were treated with azithromycin during the first trimester of pregnancy in a teratogen information service study (Bar-Oz et al., 2012). Similarly, the frequency of congenital anomalies was not increased among 113 children of women treated with azithromycin during pregnancy in another teratogen information service study in which 72% of the women took the drug during the first trimester (Sarkar et al., 2006).
No association with maternal azithromycin treatment early in pregnancy was found among 1537 male infants with hypospadias in the National Birth Defects Prevention Study (Lind et al., 2013). No association with maternal azithromycin use during the first trimester of pregnancy was found among 646 infants with isolated club foot in another North American case-control study (Werler et al., 2014).
OTHER ADVERSE PERINATAL OUTCOMES
An association with filling a prescription for azithromycin during early pregnancy was observed among 8702 women who had spontaneous abortions in the Quebec record linkage study (odds ratio=1.65, 95% confidence interval 1.34-2.02 in comparison to infants of unexposed pregnancies; odds ratio=1.83, 95% confidence interval 1.30-2.56 in comparison to infants whose mothers were treated with penicillin during the first trimester) (Muanda et al., 2017b).
Adverse perinatal and neonatal outcomes were no more frequent than expected among the infants of women who were treated with azithromycin during the second trimester of pregnancy in randomized controlled trials (Pitsouni et al., 2007; van den Broek et al., 2009). Miscarriage after second-trimester genetic amniocentesis was less frequent than expected after prophylactic azithromycin treatment in another clinical trial (Giorlandino et al., 2009). No adverse effects were observed in the infants of 20 women who were treated with azithromycin less than 1-7 days before delivery (Ramsey et al., 2003).
ANIMAL TERATOLOGY STUDIES
No increase in the frequency of embryonic death or malformations was observed among the offspring of rats or mice treated during pregnancy with less than 1-10 times the maximum human therapeutic dose of azithromycin (Stadnicki et al., 1996). Selected References: Bar-Oz B, Weber-Schoendorfer C, Berlin M, Clementi M, Di Gianantonio E, de Vries L, De Santis M, Merlob P, Stahl B, Eleftheriou G, Manakova E, Hubickova-Heringova L, Youngster I, Berkovitch M: The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observational study. Drug Saf 35(7):589-598, 2012. [E]
Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer SM, Gideon PS, Hall KS, Kaltenbach LA, Ray WA: Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol 23(1):18-28, 2009. [E]
Damkier P, Bronniche LMS, Korch-Frandsen JFB, Broe A: In utero exposure to antibiotics and risk of congenital malformations: a population-based study. Am J Obstet Gynecol 221(6):648.e1-648.e15, 2019. [E]
Dreier JW, Andersen A-MN, Berg-Beckhoff G: Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics 133(3):e674-e688, 2014. [R]
Fan H, Gilbert R, O'Callaghan F, Li L: Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study [published erratum appears in BMJ 368:m766, 2020]. BMJ 368:m331, 2020. [E]
Giorlandino C, Cignini P, Cini M, Brizzi C, Carcioppolo O, Milite V, Coco C, Gentili P, Mangiafico L, Mesoraca A, Bizzoco D, Gabrielli I, Mobili L: Antibiotic prophylaxis before second-trimester genetic amniocentesis (APGA): a single-centre open randomised controlled trial. Prenat Diagn 29(6):606-612, 2009. [E]
Lind JN, Tinker SC, Broussard CS, Reefhuis J, Carmichael SL, Honein MA, Olney RS, Parker SE, Werler MM: Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007. Pharmacoepidemiol Drug Saf 22(7):783-793, 2013. [E]
Muanda FT, Sheehy O, Berard A: Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ 189(17):E625-E633, 2017b. [E]
Muanda FT, Sheehy O, Berard A: Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study. Br J Clin Pharmacol 83(11):2557-2571, 2017a. [E]
Pitsouni E, Iavazzo C, Athanasiou S, Falagas ME: Single-dose azithromycin versus erythromycin or amoxicillin for Chlamydia trachomatis infection during pregnancy: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents 30(3):213-221, 2007. [R]
Ramsey PS, Vaules MB, Vasdev GM, Andrews WW, Ramin KD: Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol 188(3):714-718, 2003. [S]
Sarkar M, Woodland C, Koren G, Einarson ARN: Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth 6:18, 2006. [E]
Stadnicki SW, Kessedjian M-J, Stadler J, Tachibana M: Preclinical reproductive and teratology studies with azithromycin. Oyo Yakuri 51(2):85-95, 1996. [A]
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 6(12):e1000191, 2009. [E]
Werler MM, Yazdy MM, Kasser JR, Mahan ST, Meyer RE, Anderka M, Druschel CM, Mitchell AA: Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring. Am J Epidemiol 180(1):86-93, 2014. [E] |