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We read with interest the recent retrospective analysis of pregnancies in the UK who were reported to have exposure to macrolides versus those exposed to penicillin (1). As the pharmacological group of macrolides includes those erythromycin and clarithromycin with 14 member rings and azithromycin with a 15 member ring, important pharmacological differences may be found. As azithromycin shows important benefits in those with severe asthma (2), and cystic fibrosis (3), it is increasingly being used as maintenance therapy in younger women with airways disease.
The recent ERS / TSANZ position statement (4) suggested that the macrolides as a group were “probably safe”, whilst penicillins were “compatible” for use in pregnancy. The recent PloS One meta-analysis suggested that there may be a small increased risk of miscarriage with azithromycin, which was higher than that of erythromycin (5). Could the authors clarify in this new study, whether there was any difference in risks for azithromycin compared with erythromycin?
The increased risk of miscarriage observed is based on three observational studies (6-8), but in these studies the bias control for the indication was made indirectly. Also, the association of increased risks with clarithromycin and azithromycin vs erythromycin were based on a single study in which the authors conclude that: “residual confounding by severity of infection cannot be ruled out” (8).
As an older study previously examining more than 100 women prescribed azithromycin during pregnancy did not find any increased risk to the foetus (9), it is important to confirm these results with high quality studies. Ad hoc data registries can also be used for comparison of the effects of specific drugs in certain specific populations (10). We agree that the macrolide antibiotics should be used with caution to determine if there is a favourable benefit-risk relationship during pregnancy.
Your sincerely
Professor Peter Middleton, Westmead Clinical School, University of Sydney
Professor Cristina Aguilera, Servei de Farmacologia Clínica, HU Vall d'Hebron, Barcelona
Professor Vibeke Backer, Copenhagen University,
1. Fan H, Gilbert RE, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study.
BMJ 2020;368:m331
2. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, Powell H, Taylor SL, Leong LEX, Rogers GB, Simpson JL.
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial.
Lancet. 2017 Aug 12;390(10095):659-668
3. Nichols DP Odem-Davis K, Cogen JD, Goss CH, Ren CL, Skalland M, Somayaji R, Heltshe SL.
Pulmonary outcomes associated with long-term azithromycin therapy in Cystic Fibrosis.
Am J Respir Crit Care Med. 2020 Feb 15;201(4):430-437
4. Middleton PG, Gade EJ, Aguilera C, MacKillop L, Button BM, Coleman C, Johnson B, Albrechtsen C, Edenborough F, Rigau D, Gibson PG, Backer V.
ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55(2). pii: 1901208. doi: 10.1183/13993003.01208-2019.
5. Fan H, Li L, Wijlaars L, Gilbert RE
Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis. PLoS One. 2019;14(2):e0212212. doi: 10.1371/journal.pone.0212212.
6. Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A, Mastroiacova P, Mazzone T, Matsui D, Koren G.
A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15:523-5.
7. Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C, Keiding N, Poulsen HE.
Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register based nationwide cohort study. PLoS One. 2013; 8(1): e53327.
8. Muanda FT, Sheehy O, Berard A.
Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ. 2017;189(17):E625-E633. doi:10.1503/cmaj.161020.
9. Sarkar M, Woodland C, Koren G, Einarson AR.
Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006; 6: 18. doi:10.1186/1471-2393-6-18
10. Nash EF, Middleton PG; Taylor-Cousar JL
Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey
J Cyst Fibros 2020, accepted 26-02-20 doi.org/10.1016/j.jcf.2020.02.018
Competing interests:
No competing interests
03 April 2020
Peter G Middleton
Respiratory and Sleep Specialist
Cristina Aguilera, Servei de Farmacologia Clínica, HU Vall d'Hebron, Barcelona; Vibeke Backer, Copenhagen University.
Re: Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study
Dear Editor
We read with interest the recent retrospective analysis of pregnancies in the UK who were reported to have exposure to macrolides versus those exposed to penicillin (1). As the pharmacological group of macrolides includes those erythromycin and clarithromycin with 14 member rings and azithromycin with a 15 member ring, important pharmacological differences may be found. As azithromycin shows important benefits in those with severe asthma (2), and cystic fibrosis (3), it is increasingly being used as maintenance therapy in younger women with airways disease.
The recent ERS / TSANZ position statement (4) suggested that the macrolides as a group were “probably safe”, whilst penicillins were “compatible” for use in pregnancy. The recent PloS One meta-analysis suggested that there may be a small increased risk of miscarriage with azithromycin, which was higher than that of erythromycin (5). Could the authors clarify in this new study, whether there was any difference in risks for azithromycin compared with erythromycin?
The increased risk of miscarriage observed is based on three observational studies (6-8), but in these studies the bias control for the indication was made indirectly. Also, the association of increased risks with clarithromycin and azithromycin vs erythromycin were based on a single study in which the authors conclude that: “residual confounding by severity of infection cannot be ruled out” (8).
As an older study previously examining more than 100 women prescribed azithromycin during pregnancy did not find any increased risk to the foetus (9), it is important to confirm these results with high quality studies. Ad hoc data registries can also be used for comparison of the effects of specific drugs in certain specific populations (10). We agree that the macrolide antibiotics should be used with caution to determine if there is a favourable benefit-risk relationship during pregnancy.
Your sincerely
Professor Peter Middleton, Westmead Clinical School, University of Sydney
Professor Cristina Aguilera, Servei de Farmacologia Clínica, HU Vall d'Hebron, Barcelona
Professor Vibeke Backer, Copenhagen University,
1. Fan H, Gilbert RE, O’Callaghan F, Li L. Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study.
BMJ 2020;368:m331
2. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, Jenkins C, Peters MJ, Marks GB, Baraket M, Powell H, Taylor SL, Leong LEX, Rogers GB, Simpson JL.
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial.
Lancet. 2017 Aug 12;390(10095):659-668
3. Nichols DP Odem-Davis K, Cogen JD, Goss CH, Ren CL, Skalland M, Somayaji R, Heltshe SL.
Pulmonary outcomes associated with long-term azithromycin therapy in Cystic Fibrosis.
Am J Respir Crit Care Med. 2020 Feb 15;201(4):430-437
4. Middleton PG, Gade EJ, Aguilera C, MacKillop L, Button BM, Coleman C, Johnson B, Albrechtsen C, Edenborough F, Rigau D, Gibson PG, Backer V.
ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55(2). pii: 1901208. doi: 10.1183/13993003.01208-2019.
5. Fan H, Li L, Wijlaars L, Gilbert RE
Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis. PLoS One. 2019;14(2):e0212212. doi: 10.1371/journal.pone.0212212.
6. Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A, Mastroiacova P, Mazzone T, Matsui D, Koren G.
A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15:523-5.
7. Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, Torp-Pedersen C, Keiding N, Poulsen HE.
Clarithromycin in early pregnancy and the risk of miscarriage and malformation: a register based nationwide cohort study. PLoS One. 2013; 8(1): e53327.
8. Muanda FT, Sheehy O, Berard A.
Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ. 2017;189(17):E625-E633. doi:10.1503/cmaj.161020.
9. Sarkar M, Woodland C, Koren G, Einarson AR.
Pregnancy outcome following gestational exposure to azithromycin. BMC Pregnancy Childbirth. 2006; 6: 18. doi:10.1186/1471-2393-6-18
10. Nash EF, Middleton PG; Taylor-Cousar JL
Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey
J Cyst Fibros 2020, accepted 26-02-20 doi.org/10.1016/j.jcf.2020.02.018
Competing interests: No competing interests