Macrolides and the placenta

To the Editor,

In the recent review of antimicrobial treatment during pregnancy, Lamont and colleagues [1] state that “They [macrolides] freely cross the placenta…” The reference [2] cited by the authors only states that macrolides cross the placenta and then begins a chain of referencing earlier sources which demonstrate that fetal blood levels of macrolides are quite lower than maternal blood levels after administration of macrolides in pregnancy [3,4].

The in vitro placental cotyledon perfusion model used by Heikkinen et al. [3] showed limited transplacental transfer of macrolides, including azithromycin. Ramsey’s group also demonstrated low fetal serum and amniotic fluid levels of azithromycin in a study of term gravid women [4].

International guidelines continue to recommend against the use of macrolides for treatment of syphilis in pregnancy due to the long-recognized lack of placental penetration clinically. Until and unless additional data become available, clinicians should not use macrolides to treat infections in pregnancy if there is a concern for transplacental passage of the infection.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Bibliography

• Lamont HF, Blogg HJ, Lamont RF. Safety of antimicrobial treatment during pregnancy: a current review of resistance, immunomodulation and teratogenicity. Expert Opin Drug Saf 2014;13(12):1569-82
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• Bahat Dinur A, Koren G, Matok I, et al. Fetal safety of macrolides. Antimicrob Agents Chemother 2013;57(7):3307-11
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• Heikkinen T, Laine K, Neuvonen PJ, et al. The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin. BJOG 2000;107(6):770-5
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• Ramsey PS, Vaules MB, Vasdev GM, et al. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obster Gynecol 2003;188(3):714-18
   PubMed Web of Science ®Google Scholar

Author's response

Ronald F Lamont BSc MB ChB MD FRCOG^†1,2

Henrietta J Blogg BA³

Harriet F Lamont BSc³

^b1University College London, Northwick Park Institute of Medical Research Campus, Division of Surgery, London, UK [phone]; [phone]; [email protected]

^c3University of Southern Denmark, Institute of Clinical Research, Odense, Denmark

^d3University of Southampton, Faculty of Medicine, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, England

^†Author for correspondence

To the Editor,

We are grateful to Drs Gelfand & Cleveland for their comments that are a valued contribution to the peer review process.

We qualified our statement that ‘macrolides freely cross the placenta’ by stating that there may be gestational age-related pharmacokinetic variation [1]. The clinical study cited by Drs Gelfand & Cleveland [2] was specific to azithromycin used in 20 women undergoing elective cesarean section at term who were given 1 g of oral azithromycin 6, 12, 24, 72, or 168 h before the operation. Azithromycin levels in placental tissue were higher than in maternal serum and sustained for up to 72 h after administration. Amniotic fluid levels of azithromycin were highest at 6 h and declined rapidly. The authors concluded, “azithromycin may have potential use for the treatment of perinatal infections”.

We made no specific mention of treatment of syphilis in pregnancy and without knowing to which international guidelines they are referring to, we are unable to comment. However, guidelines are educational aids to good clinical practice and are not intended to be prescriptive directions defining a single course of management. In addition, guidelines based on retrospective analyses of pooled data are only as good as the quality of studies included [3]. We cited a number of macrolide studies in which no meaningful association between their use and congenital malformations were found. This included one large study involving over 100,000 pregnancies, of which ∼ 1000 were exposed to macrolides in which no association was found between macrolides and congenital malformations, perinatal mortality, low birth weight, low Apgar score or preterm birth [2]. If these studies were not included in the guidelines to which Drs Gelfand & Cleveland refer, perhaps they should be. Finally, we did state in our conclusion of the macrolide section that, as there is relatively little or mixed data on macrolides such as clarithromycin, azithromycin and roxithromycin, these should be used with more caution until larger studies are available.