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Concerns about the safety of nicotine replacement therapy during pregnancy on lung development in children

Published:October 22, 2016DOI:https://doi.org/10.1016/j.ajog.2016.10.023
      To the Editors:
      We read with great interest the article “Success of smoking cessation interventions during pregnancy.”
      • Bérard A.
      • Zhao J.-P.
      • Sheehy O.
      Success of smoking cessation interventions during pregnancy.
      Bérard et al
      • Bérard A.
      • Zhao J.-P.
      • Sheehy O.
      Success of smoking cessation interventions during pregnancy.
      evaluated the effect of nicotine replacement therapy (NRT) during pregnancy and found that NRT had a favorable impact on smoking cessation rates in expectant mothers. In addition, this retrospective cohort study also showed a reduction in premature birth rates and small for gestational age. However, so far, evidence from trials of pharmacologic interventions failed to show a positive impact on neonatal outcomes.
      • Coleman T.
      • Chamberlain C.
      • Davey M.A.
      • Cooper S.E.
      • Leonardi-Bee J.
      Pharmacological interventions for promoting smoking cessation during pregnancy.
      We agree with the authors that smoking cessation is of utmost importance in improving neonatal outcomes. However, the intervention that was offered should have been unambiguously proven to be both effective and safe for short- and long-term endpoints. We disagree with Bérard et al that NRT is a good option for helping pregnant women quit smoking. Our concerns (based on animal studies) focus on its potential long-term pulmonary consequences.
      Elastin is an extremely long-living protein that plays a crucial role in the lungs. Elastin’s precursor tropoelastin is mainly synthesized perinatally after which the production is suppressed. Once tropoelastin has been produced, it is secreted into the extracellular matrix and aligned with other tropoelastin proteins into elastin fibers. Subsequently, elastin fibers have to be crosslinked with each other by the enzyme lysyl oxidase (LO). LO crosslinking is a crucial step in elastogenesis. Whereas crosslinked elastin is relatively resistant to degradation by elastases, uncrosslinked elastin is extremely vulnerable to these destructive enzymes. Furthermore, elastin only acquires its full elastic properties after proper LO-crosslinking.
      Nicotine inhibits LO activity thereby interfering with elastin crosslinking.
      • Maritz G.S.
      • Windvogel S.
      Is maternal copper supplementation during alveolarization protecting the developing rat lung against the adverse effects of maternal nicotine exposure? A morphometric study.
      Although nicotine during pregnancy has been shown not to have a significant effect on fetal growth, it does have an unfavorable effect on lung development.
      • Maritz G.S.
      • Windvogel S.
      Is maternal copper supplementation during alveolarization protecting the developing rat lung against the adverse effects of maternal nicotine exposure? A morphometric study.
      The age of pulmonary elastin corresponds with the age of a subject and there is usually no substantial elastoneogenesis in the lungs after the perinatal period.
      • Shapiro S.D.
      • Endicott S.K.
      • Province M.A.
      • Pierce J.A.
      • Campbell E.J.
      Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon.
      It is therefore likely that subjects who produce inadequate amounts of crosslinked elastin in utero have an increased likelihood of the development of chronic obstructive pulmonary disease (a respiratory disease characterized by loss of elasticity) as adults.
      We propose a large intervention trial to be undertaken in order to assess the short- and long-term effects of NRT compared to placebo or against psychosocial interventions. In our opinion, pregnant women should not be advised to use NRT until it has been proved unequivocally that this intervention does not lead to adverse long-term pulmonary effects in their children.

      References

        • Bérard A.
        • Zhao J.-P.
        • Sheehy O.
        Success of smoking cessation interventions during pregnancy.
        Am J Obstet Gynecol. 2016; 215: 611.e1-611.e8
        • Coleman T.
        • Chamberlain C.
        • Davey M.A.
        • Cooper S.E.
        • Leonardi-Bee J.
        Pharmacological interventions for promoting smoking cessation during pregnancy.
        Cochrane Database Syst Rev. 2015; 12: CD010078
        • Maritz G.S.
        • Windvogel S.
        Is maternal copper supplementation during alveolarization protecting the developing rat lung against the adverse effects of maternal nicotine exposure? A morphometric study.
        Exp Lung Res. 2003; 29: 243-260
        • Shapiro S.D.
        • Endicott S.K.
        • Province M.A.
        • Pierce J.A.
        • Campbell E.J.
        Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon.
        J Clin Invest. 1991; 87: 1828-1834

      Linked Article

      • Success of smoking cessation interventions during pregnancy
        American Journal of Obstetrics & GynecologyVol. 215Issue 5
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          Smoking during pregnancy is a modifiable risk factor associated with adverse pregnancy outcomes. Smoking during pregnancy has been shown to increase the risk of spontaneous abortion, prematurity, low birthweight, congenital malformations, and sudden infant death syndrome. Despite the fact that it is well known that smoking can lead to adverse pregnancy outcomes, 13-25% of pregnant women overall continue to smoke during this critical period.
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      • Reply
        American Journal of Obstetrics & GynecologyVol. 216Issue 3
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          We thank Drs Janssen and Oudijk for their comment on our article on the use of smoking cessation interventions during gestation among pregnant smokers.1 However, their comments are based on animal studies and have limited clinical implications; furthermore, they do not provide comparative data with the effect of smoking itself. Furthermore, Janssen and Oudijk falsely interpret a non–statistically significant increased risk as “no positive effect” in the only human data that they gave as supporting documentation.
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