- Email: [email protected]
Maternal antibiotic use and risk of asthma in offspring
Correspondence
NO2 in the lungs: a weighty matter
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
As an atmospheric chemist interested in health, I read David Holmes’ 1 report on air quality in the UK with interest. I feel a need to clarify the statement “NO2 is heavier than CO2 and accumulates in the lungs where it turns to nitric acid”. The statement could be interpreted to mean that the difference in molecular weight of NO 2 versus CO 2 (2 [of 46] Da heavier) would have an effect on its retention in the lungs (or distribution in the atmosphere for that matter). However, the forces associated with macroscopic air motions (wind, inhalation, and exhalation) are many times bigger than are density differences, and will cancel any local density differences in the lungs. Also, although formation of nitric acid does happen when NO2 dissolves in water (nitrous acid is the other product), the health effects of NO2 are thought to be much more complicated and relate to protein nitration, perhaps preceded by reactive oxygen species chemistry. These points aside, NO2 exposure, especially near roads, is clearly an important area of concern in understanding of the health effects of air pollution. I declare no competing interests.
James M Roberts [email protected] Chemical Sciences Division, National Oceanic and Atmospheric Administration, Earth System Research Laboratory, Boulder, CO, USA 1
Holmes D. Air quality gives UK Government a headache. Lancet Respir Med 2014; 2: 606.
Maternal antibiotic use and risk of asthma in offspring Jakob Stokholm and colleagues 1 reported a large study of the relation between maternal antibiotic use and the risk of asthma in their offspring based on the 200 week period before, e16
during, and after the child’s birth. That antibiotic use in every period was associated with essentially the same increased risk of asthma led the authors to conclude that the effects on asthma were due to a general maternal propensity for infection, and that antibiotic use, in effect, is a marker for this. However, there are clear alternative hypotheses for the increased and dose-related asthma risk. Gestational or pregestational antibiotics might change the maternal microbiota at the time of birth; Stokholm and colleagues discuss this theory but discount its importance. However, this general concept is consistent with a 2002 Danish report that changes in the maternal vaginal microbes were associated with wheezing and asthma in children.2 Postnatal maternal antibiotics reach the infant via maternal milk, and when mothers pre-masticate food via oral secretions, providing other mechanisms for perturbation. In addition, higher antibiotic use by mothers might be a marker for an increased propensity for antibiotic drug prescriptions in children. Maternal antibiotic use, which is rarely a medical absolute, shows a propensity of some women and their doctors to use antibiotics liberally. This same propensity might be mirrored in medical approaches to their children’s illnesses. Early in-utero exposures can lead to changed organogenesis and fetal development—eg, maternal antibiotic use has been associated with changes in infant birthweight,3 increased allergic diseases, 4 and changed methylation levels in imprinted genes. 5 To the extent that there is a viable placental microbiome, 6 prenatal antibiotics would have selective effects too. None of these hypotheses are exclusive, and all are testable, especially in the setting of the kinds of registries that Stokholm and colleagues used. Use of an altered
microbiome to explain the findings with similar effect sizes for each of the periods of study is consistent with the theory that the changes in the microbiome that have been noted in recent years are cumulative across generations, 7 and is also consistent with experimental models that early life antibiotic exposures might transiently affect gut microbial community structure with longterm metabolic and immunological phenotypes.8 These models indicate an early life developmental window in which antibiotic exposure interferes with healthy metabolic and immune maturation. We declare no competing interests.
*Martin J Blaser, Maria Gloria Dominguez Bello [email protected] Human Microbiome Program, NYU Langone Medical Center, New York, NY 10016, USA 1
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8
Stokholm J, Sevelsted A, Bønnelykke K, Bisgaard H. Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study. Lancet Respir Med 2014; 2: 631–37. Benn CS, Thorsen P, Jensen JS, et al. Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol 2002; 110: 72–77. Czeizel AE, Rockenbauer M, Olsen J. Use of antibiotics during pregnancy. Eur J Obstet Gynecol Reprod Biol 1998; 81: 1–8. McKeever TM, Lewis SA, Smith C, Collins J, Heatlie H, Frischer M, et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. J Allergy Clin Immunol 2002; 109: 43–50. Vidal AC, Murphy SK, Murtha AP, et al. Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring. Int J Obes (Lond) 2013; 37: 907–13. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med 2014; 6: 237ra65. Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 2009; 7: 887–94. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158: 705–21.
www.thelancet.com/respiratory Vol 2 October 2014
NO2 in the lungs: a weighty matter
If you would like to respond to an article published in The Lancet Respiratory Medicine, please submit your correspondence online at: http:// ees.elsevier.com/thelancetrm
As an atmospheric chemist interested in health, I read David Holmes’ 1 report on air quality in the UK with interest. I feel a need to clarify the statement “NO2 is heavier than CO2 and accumulates in the lungs where it turns to nitric acid”. The statement could be interpreted to mean that the difference in molecular weight of NO 2 versus CO 2 (2 [of 46] Da heavier) would have an effect on its retention in the lungs (or distribution in the atmosphere for that matter). However, the forces associated with macroscopic air motions (wind, inhalation, and exhalation) are many times bigger than are density differences, and will cancel any local density differences in the lungs. Also, although formation of nitric acid does happen when NO2 dissolves in water (nitrous acid is the other product), the health effects of NO2 are thought to be much more complicated and relate to protein nitration, perhaps preceded by reactive oxygen species chemistry. These points aside, NO2 exposure, especially near roads, is clearly an important area of concern in understanding of the health effects of air pollution. I declare no competing interests.
James M Roberts [email protected] Chemical Sciences Division, National Oceanic and Atmospheric Administration, Earth System Research Laboratory, Boulder, CO, USA 1
Holmes D. Air quality gives UK Government a headache. Lancet Respir Med 2014; 2: 606.
Maternal antibiotic use and risk of asthma in offspring Jakob Stokholm and colleagues 1 reported a large study of the relation between maternal antibiotic use and the risk of asthma in their offspring based on the 200 week period before, e16
during, and after the child’s birth. That antibiotic use in every period was associated with essentially the same increased risk of asthma led the authors to conclude that the effects on asthma were due to a general maternal propensity for infection, and that antibiotic use, in effect, is a marker for this. However, there are clear alternative hypotheses for the increased and dose-related asthma risk. Gestational or pregestational antibiotics might change the maternal microbiota at the time of birth; Stokholm and colleagues discuss this theory but discount its importance. However, this general concept is consistent with a 2002 Danish report that changes in the maternal vaginal microbes were associated with wheezing and asthma in children.2 Postnatal maternal antibiotics reach the infant via maternal milk, and when mothers pre-masticate food via oral secretions, providing other mechanisms for perturbation. In addition, higher antibiotic use by mothers might be a marker for an increased propensity for antibiotic drug prescriptions in children. Maternal antibiotic use, which is rarely a medical absolute, shows a propensity of some women and their doctors to use antibiotics liberally. This same propensity might be mirrored in medical approaches to their children’s illnesses. Early in-utero exposures can lead to changed organogenesis and fetal development—eg, maternal antibiotic use has been associated with changes in infant birthweight,3 increased allergic diseases, 4 and changed methylation levels in imprinted genes. 5 To the extent that there is a viable placental microbiome, 6 prenatal antibiotics would have selective effects too. None of these hypotheses are exclusive, and all are testable, especially in the setting of the kinds of registries that Stokholm and colleagues used. Use of an altered
microbiome to explain the findings with similar effect sizes for each of the periods of study is consistent with the theory that the changes in the microbiome that have been noted in recent years are cumulative across generations, 7 and is also consistent with experimental models that early life antibiotic exposures might transiently affect gut microbial community structure with longterm metabolic and immunological phenotypes.8 These models indicate an early life developmental window in which antibiotic exposure interferes with healthy metabolic and immune maturation. We declare no competing interests.
*Martin J Blaser, Maria Gloria Dominguez Bello [email protected] Human Microbiome Program, NYU Langone Medical Center, New York, NY 10016, USA 1
2
3
4
5
6
7
8
Stokholm J, Sevelsted A, Bønnelykke K, Bisgaard H. Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study. Lancet Respir Med 2014; 2: 631–37. Benn CS, Thorsen P, Jensen JS, et al. Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol 2002; 110: 72–77. Czeizel AE, Rockenbauer M, Olsen J. Use of antibiotics during pregnancy. Eur J Obstet Gynecol Reprod Biol 1998; 81: 1–8. McKeever TM, Lewis SA, Smith C, Collins J, Heatlie H, Frischer M, et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. J Allergy Clin Immunol 2002; 109: 43–50. Vidal AC, Murphy SK, Murtha AP, et al. Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring. Int J Obes (Lond) 2013; 37: 907–13. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med 2014; 6: 237ra65. Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 2009; 7: 887–94. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158: 705–21.
www.thelancet.com/respiratory Vol 2 October 2014