Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: authors’ reply

Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring:... We thank Chandrakumar et al. for their interest in our work.1 We acknowledge some issues raised in the original manuscript and will address other points in detail that the manuscript word limit precluded. In addition to the established effects on the maternal microbiome,2 antibiotics before and during pregnancy may also be indicative of increased underlying susceptibility to infection. This susceptibility may further increase the risk of offspring infection beyond that from antibiotic-induced dysbiosis. Data on infections in pregnancy not treated with antibiotics would be informative in disentangling the relative contributions, but these data are not available. As pre-pregnancy infection may be more indicative of an underlying susceptibility to infection in the mother (pregnancy itself increases the risk of infection per se3), we therefore adjusted for pre-pregnancy antibiotic use in the analysis of the risk associated with antibiotics in pregnancy. The association between pregnancy antibiotics and offspring infection attenuated somewhat, suggesting that an underlying susceptibility to infection, manifesting by increased antibiotic use, contributes modestly but does not fully explain the association between pregnancy antibiotics and offspring infection. We cannot fully concur with the other interpretations suggested. We did not compare the risk associated with pre-pregnancy and pregnancy antibiotic exposures, as the more meaningful comparison group is mothers unexposed to antibiotics during these periods. The observation that the overall risks were similar for offspring of mothers who had antibiotics only before pregnancy or only during pregnancy is not informative about possible underlying mechanisms. The risk doubled if the mothers were exposed during both periods, implying that there are additive effects. An underlying susceptibility to infection would be unlikely to show a time-dependent effect; therefore, the risk before pregnancy would not increase once antibiotic exposure in pregnancy was also considered. The cumulative risk from pre-pregnancy plus pregnancy antibiotic exposure may reflect both an underlying susceptibility and antibiotic-related dysbiosis. In infants delivered by caesarean section, who do not receive the maternal enteric microbiome but a microbiome predominantly from maternal skin and the hospital environment, an effect of pregnancy antibiotics on postnatal offspring infection would not be expected, as these infants do not receive a dysbiotic maternal enteric microbiome. The contribution, if any, from potentially antibiotic-affected skin flora on infection risk is unknown, but is likely to be less. We acknowledge the importance of breastfeeding in infection susceptibility; unfortunately, these data are unavailable. Postnatal antibiotic exposure in the mother may be informative about her underlying susceptibility to infection, but interpretation of these analyses is likely to be complicated by the likelihood that young children infect other family members and vice versa. References 1 Miller JE , Wu C , Pedersen LH , de Klerk N , Olsen J , Burgner DP. Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study . Int J Epidemiol 2018 ; 47 : 561 – 71 . Google Scholar CrossRef Search ADS PubMed 2 Clemente JC , Ursell LK , Parfrey LW , Knight R. The impact of the gut microbiota on human health: an integrative view . Cell 2012 ; 148 : 1258 – 70 . Google Scholar CrossRef Search ADS PubMed 3 Jamieson DJ , Theiler RN , Rasmussen SA. Emerging infections and pregnancy . Emerg Infect Dis 2006 ; 12 : 1638 – 43 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Epidemiology Oxford University Press

Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: authors’ reply

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Publisher
Oxford University Press
Copyright
© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
ISSN
0300-5771
eISSN
1464-3685
D.O.I.
10.1093/ije/dyy097
Publisher site
See Article on Publisher Site

Abstract

We thank Chandrakumar et al. for their interest in our work.1 We acknowledge some issues raised in the original manuscript and will address other points in detail that the manuscript word limit precluded. In addition to the established effects on the maternal microbiome,2 antibiotics before and during pregnancy may also be indicative of increased underlying susceptibility to infection. This susceptibility may further increase the risk of offspring infection beyond that from antibiotic-induced dysbiosis. Data on infections in pregnancy not treated with antibiotics would be informative in disentangling the relative contributions, but these data are not available. As pre-pregnancy infection may be more indicative of an underlying susceptibility to infection in the mother (pregnancy itself increases the risk of infection per se3), we therefore adjusted for pre-pregnancy antibiotic use in the analysis of the risk associated with antibiotics in pregnancy. The association between pregnancy antibiotics and offspring infection attenuated somewhat, suggesting that an underlying susceptibility to infection, manifesting by increased antibiotic use, contributes modestly but does not fully explain the association between pregnancy antibiotics and offspring infection. We cannot fully concur with the other interpretations suggested. We did not compare the risk associated with pre-pregnancy and pregnancy antibiotic exposures, as the more meaningful comparison group is mothers unexposed to antibiotics during these periods. The observation that the overall risks were similar for offspring of mothers who had antibiotics only before pregnancy or only during pregnancy is not informative about possible underlying mechanisms. The risk doubled if the mothers were exposed during both periods, implying that there are additive effects. An underlying susceptibility to infection would be unlikely to show a time-dependent effect; therefore, the risk before pregnancy would not increase once antibiotic exposure in pregnancy was also considered. The cumulative risk from pre-pregnancy plus pregnancy antibiotic exposure may reflect both an underlying susceptibility and antibiotic-related dysbiosis. In infants delivered by caesarean section, who do not receive the maternal enteric microbiome but a microbiome predominantly from maternal skin and the hospital environment, an effect of pregnancy antibiotics on postnatal offspring infection would not be expected, as these infants do not receive a dysbiotic maternal enteric microbiome. The contribution, if any, from potentially antibiotic-affected skin flora on infection risk is unknown, but is likely to be less. We acknowledge the importance of breastfeeding in infection susceptibility; unfortunately, these data are unavailable. Postnatal antibiotic exposure in the mother may be informative about her underlying susceptibility to infection, but interpretation of these analyses is likely to be complicated by the likelihood that young children infect other family members and vice versa. References 1 Miller JE , Wu C , Pedersen LH , de Klerk N , Olsen J , Burgner DP. Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: a population-based cohort study . Int J Epidemiol 2018 ; 47 : 561 – 71 . Google Scholar CrossRef Search ADS PubMed 2 Clemente JC , Ursell LK , Parfrey LW , Knight R. The impact of the gut microbiota on human health: an integrative view . Cell 2012 ; 148 : 1258 – 70 . Google Scholar CrossRef Search ADS PubMed 3 Jamieson DJ , Theiler RN , Rasmussen SA. Emerging infections and pregnancy . Emerg Infect Dis 2006 ; 12 : 1638 – 43 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

International Journal of EpidemiologyOxford University Press

Published: May 30, 2018

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