Motherisk Int J 2020;1:12
Elif Keskin-Arslan MD (1,2), Yusuf Cem Kaplan MD (1,2), Gideon Koren MD (3, 4)
Terafar - Izmir Katip Celebi University Teratology Information Center, Turkey (1) . Department of Pharmacology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, Turkey (2), Adelson Faculty of Medicine, Ariel University(3) and Motherisk Israel Program (4)
I notice that azithromycin has been increasingly included in the treatment regimens of coronavirus disease 2019 (COVID-19) by clinicians despite debates regarding its efficacy in COVID-19. Does azithromycin pose a risk to the fetus? Is it compatible with breastfeeding?
Azithromycin is semi-synthetic macrolide derived from erythromycin used in the treatment of community-acquired pneumonia, Shigella and upper respiratory infection in pregnant women with a history of penicillin allergy . It is also a first line treatment of urogenital infections due to chlamydia and gonorrhea during pregnancy (1).
Azithromycin has been shown to possess antiviral, anti-inflammatory, and immunomodulatory effects (2, 3) that may explain the growing interest for its use as part of the treatment of SARS-CoV-2 coronavirus (4). A recent study by Gautret et al. reported the clinical and microbiological effectiveness of hydroxychloroquine and azithromycin combination in the treatment of COVID-19 patients (5). The paper consequently received high attention, however several questions regarding its methodology have been raised necessitating further evidence of effectiveness (6).
Azithromycin has not been associated with an increased risk of malformations in animal studies (7). It has been shown to have a relatively low rate of in vitro transplacental passage (2.6%) (8). Umbilical arterial and venous azithromycin levels were demonstrated to be 20-50% lower than maternal serum levels (9).
To date, the majority of observational studies suggested no significant associations between prenatal azithromycin use and major congenital malformations (10-14). However, a trend towards increase in the rate of malformations was also seen in a few studies. For instance, in the cohort study by Bar-Oz et al a small number of azithromycin exposed women (n=156) was compared to women with non-teratogenic drug exposures and a non-significant trend towards increase risks was observed for both major congenital malformations (OR 2.23; 95% CI 0.91-5.50) and heart defects (OR 3.59; 95% CI 0.99-12.88]) (15). An important recent cohort study by Damkier et al. assessed a large number of pregnancies with macrolide exposure (erythromycin; n=5563, azithromycin; n=5037, roxithromycin; n=3027). The authors reported a small yet statistically significant increase in risk of major congenital malformations (OR 1.19; 95% CI 1.03-1.08) and a non-significant trend towards increase for cardiac malformations (OR 1.29; 95% CI 0.99-1.67) when the exposed women was compared with unexposed women (14). However when exposed women were compared to penicillin exposed women (disease match controls) the point estimates for both outcomes decreased and the OR for major malformations became non-significant (MCM: OR 1.09; 95% CI 0.93-1.27, cardiac malformation: OR 1.14; 95% CI 0.86-1.51) (16).
To date, there are also four meta-analyses investigating major malformations following macrolide exposure during pregnancy (17-20), which have used different methodology and reported inconsistent findings. Among those, the meta-analysis by Fan et al. reported some significant associations between azithromycin exposure and major malformations and miscarriage (18). However, although this paper was a meta-analysis, the “pooled” data for azithromycin was coming form only one study and the extracted data were not adjusted for maternal confounders. Therefore, this result cannot be considered as a “meta-analytic result for azithromycin and remains questionable. Recent preliminary findings from a meta-analysis by our team detected, similar to Damkier et al, a slight yet significant increase in risk of major congenital malformations (OR 1.25; 95% CI 1.05–1.49) following azithromycin exposure during pregnancy (19). The OR for the risk of heart defects were non-significant (OR 1.21; 95% CI 0.74–2.00) (19). However the contribution of maternal confounders could not be definitively ruled out. In another meta-analysis, the pooled data of two cohort studies have not shown a significantly increased risk for major congenital malformation or heart defects following prenatal azithromycin exposure (ORmix control group 1.09; 95% CI 1.00–1.19) (20).
Other adverse pregnancy outcomes There is only one nested case-control study evaluating the rates of spontaneous abortions following azithromycin exposure, showing a moderate and significant increased risk (aOR 1.65, 95% CI 1.34–2.02) (21).
Inconsistent results exist regarding the association of infantile hypertrophic pyloric stenosis (IHPS) following macrolide exposure, particularly erythromycin, during pregnancy (22,23).
The study by Meeraus et al. reported a 1.7 fold increase for cerebral palsy or epilepsy (24) while three other studies reported an approximately 1.2-1.3 fold increase for asthma following macrolide exposure during pregnancy (25-27). However, further data are needed before confirming these associations as causal since inconsistent findings, particularly for the association of prenatal antibiotic use and childhood asthma, exist. Furthermore, several confounders such as genetics, environmental and paternal exposures, infections and disruption of maternal microbiota should be better addressed.
A key parameter for evaluating the safety of medications during breastfeeding is the Relative Infant Dose (RID) which is calculated by dividing the dose that the infant is exposed to via milk by the weight-adjusted dose of the mother. An RID of less than 10% is generally considered safe for breastfeeding (28). Hale reported a RID of 5.9 % for azithromycin (29). Pharmacokinetic studies regarding the passage of azithromycin into breast milk and its' maternal levels were based on data of approximately 50 women who received single dose azithromycin (500 mg or 2 g) during labor (30). In modelling studies it was predicted that the infant would be exposed to an average dose of 0.1-1.2 mg /kg/day (30). These levels are lower than the usual treatment doses for infants. According to the simulated a maternal dosage regimen, weight-adjusted dosage of azithromycin was found to be 2.2% and 2.9% of the maternal dosage, respectively (31).
Some concerns exist regarding the possible association between IHPS and mother’s or infant’s use of macrolides during the postnatal period. According to results of three meta-analyses, postnatal infants’ macrolide use (22), particularly erythromycin exposure for the first two weeks (23, 32) were associated with an increased risk for IHPS.
Azithromycin exposure during breastfeeding was noted in four studies. IHPS has not been reported in two studies with limited azithromycin exposures (n=20 and n=10) (31, 33).
A Danish cohort study which was comprised of 1116 macrolide- prescribed women (erythromycin; n=1012, spiramycin; n=3, roxithromycin; n=268, clarithromycin; n=24, azithromycin; n=101) within 90 days postpartum, reported a 2.3 to 3 fold non-significant increase of rate for IHPS (34). Further stratification of the infants yielded an OR of 10.3 for girls and 2.0 for boys. However no subgroup analysis regarding specific macrolides was made and less than 10% of the exposures were to azithromycin. In addition, no information was given regarding the specific macrolide used by the affected infants (34). A more recent Danish study evaluated macrolide use during pregnancy (n=30091), breastfeeding (n=21557) and also in infants(n=6591). Macrolide use in both infants and mothers during days 0 to 13 after birth was associated with IHPS in this study (35). A significant increase in risk of IHPS was noted in subgroup analysis of azithromycin exposure during postnatal days 0 to 13 (RR 10.3; 95% CI 3.31-32.3) (35).
In contrast, two recent meta-analyses did not detect a significant association between maternal macrolide use during breastfeeding and IHPS (22,23).
The majority of existing observational studies have not suggested clinically significant associations between prenatal azithromycin exposure and major congenital malformations. As shown by Damkier et al., the associations reported by a few studies might well be attributable to maternal confounders (16, 19). To date a single study suggested an approximately 1.5-fold increase in the rate of spontaneous abortions which needs further confirmation. Therefore, azithromycin can be used for the treatment of critical infections during pregnancy when clinically indicated.
Azithromycin is compatible with breastfeeding from the RID perspective, since its measured and simulated RID is low and it has been used in higher doses for the treatment of infections in infants. The suggested association between macrolide use during breastfeeding and IHPS needs further confirmation. However, the infant should be monitored for early signs of IHPS (30).
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