Pregnancy outcome after gestational exposure to erythromycin – a population‐based register study from Norway

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• It has generally been regarded as safe to take erythromycin during pregnancy. A recent study from Sweden found that erythromycin exposure in the first trimester was associated with congenital cardiovascular defects. The results led to warnings against using erythromycin in the first trimester from both the Swedish and Norwegian governments. WHAT THIS STUDY ADDS• This large, population-based register study did not find that erythromycin or macrolide use in pregnancy was significantly associated with congenital malformations, cardiovascular malformations or any other specific malformation. AIMSErythromycin is a macrolide antibiotic indicated for respiratory tract infections, genital chlamydia and skin infections. It has recently been suggested that erythromycin use in the first trimester of pregnancy can increase the risk of congenital cardiovascular malformations. This study aimed to determine whether erythromycin exposure in the first trimester is associated with cardiovascular or other malformations. METHODSWe studied 180 120 women in Norway who were pregnant during [2004][2005][2006][2007]. Data on all live births stillbirths and induced abortions after 12 gestational weeks from The Medical Birth Registry of Norway (MBRN) were linked to information from the Norwegian prescription database (NorPD). We compared the pregnancy outcomes of women who had taken erythromycin (n = 1786, 1.0%), penicillin V (n = 4921, 2.7%) or amoxicillin (n = 1599, 0.9%) in their first trimester with outcomes of women who had not taken any systemic antibiotics (n = 163 653, 90.9%) during this period. RESULTSThe risk of cardiovascular malformations was not significantly different with or without exposure to erythromycin in the first trimester (adjusted OR = 1.2 [95% CI 0.8, 1.8]) or in the most vulnerable period of heart formation (adjusted OR = 1.6 [95% CI 0.9-3.0]). Sub-analyses showed that the risk for any specific malformations was not increased with erythromycin, macrolides, penicillin V or amoxicillin compared with no antibiotic use in first trimester. CONCLUSIONSThis large, population-based register study did not find that exposure to erythromycin or macrolides in the first trimester of pregnancy was associated with fetal cardiovascular or other malformations. These results suggest that the risk of erythromycin use during early pregnancy, if any, is low.

Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

“…AZ has a number of pharmacokinetic properties that make it well suited to use in pregnancy infections (21); it has an extended tissue half-life (ϳ68 h) and has been shown to accumulate in leukocytes, potentially amplifying its ef-ficacy in treating infection (21). AZ has an excellent safety profile; reports of hepatotoxicity following AZ administration (22) are uncommon, its use is not associated with fetal abnormalities or malformations (23,24), and it is well tolerated in patients with compromised renal function (21). A recent population level study in Denmark concluded that the small absolute risk of tachyarrhythmia derived from potential Q-T period elongation in highrisk individuals (25) is not significant in young and middle-aged adults (i.e., the normal pregnant population) (26).…”

Fetal Safety of Macrolides

“…The macrolides cross the placenta, and their clearance rate in pregnancy is faster in late pregnancy (9,10). Several studies conducted over the last 50 years failed to show an association between the use of erythromycin in the first trimester of pregnancy and the risk of major malformations for the most part (11)(12)(13). In contrast, a widely publicized Swedish study reported increased risk of cardiovascular malformations, leading several Scandinavian countries to avoid prescribing the drug to pregnant women (14).…”

Effect of azithromycin on fetal development in rats

“…These results were previously seen as azithromycin caused neural tube defects, maxillary deformity and situs inverses (Karabulut et al, 2008). It was concluded that exposure to erythromycin or macrolides in the first trimester of pregnancy was associated with fetal cardiovascular or other malformations (Maria et al, 2012). Also tilmicosin caused some visceral defects (Abo-Kora et al, 2016).…”