Developing a taxonomy to describe offspring outcomes in studies involving pregnant mammals’ exposure to non-tobacco nicotine: A systematic scoping review

PLOS ONE RESEARCH ARTICLE Developing a taxonomy to describe offspring outcomes in studies involving pregnant mammals’ exposure to non-tobacco nicotine: A systematic scoping review Lucy Phillips ID1*, Ross Thomson1, Tom Coleman-Haynes1, Sue Cooper1, Felix Naughton2, Lisa Mcdaid2, Joanne Emery2, Tim Coleman1 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Centre for Academic Primary Care, University of Nottingham, Nottingham, United Kingdom, 2 School of Health Sciences, University of East Anglia, Norwich, United Kingdom * Abstract OPEN ACCESS Citation: Phillips L, Thomson R, Coleman-Haynes T, Cooper S, Naughton F, Mcdaid L, et al. (2023) Developing a taxonomy to describe offspring outcomes in studies involving pregnant mammals’ exposure to non-tobacco nicotine: A systematic scoping review. PLoS ONE 18(2): e0280805. https://doi.org/10.1371/journal.pone.0280805 Editor: Saeed Ahmed, Rutland Regional Medical Center, UNITED STATES Received: February 22, 2022 Accepted: January 8, 2023 Published: February 3, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0280805 Copyright: © 2023 Phillips et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Introduction Many countries recommend Nicotine Replacement Therapy (NRT) for smoking cessation in pregnancy. Preclinical studies of nicotine exposure to pregnant mammals could indicate how nicotine may adversely affect the developing fetus. As a first step towards summarising this literature, we undertook a systematic scoping review to determine the number and nature of offspring outcomes studied. Methods We searched MEDLINE and EMBASE databases for papers reporting empirical data on offspring outcomes following nicotine exposure to pregnant non-human mammals. We excluded studies that investigated exposure to only smoking, e-cigarettes, nicotine vaccines, or studies with no ‘nicotine only’ group. We developed a draft taxonomy and using this, described and quantified outcomes reported. Results We identified 476 studies, which reported 729 offspring outcomes. The draft taxonomy classified outcomes as being measured in i) whole animals, ii) body systems and iii) ‘other’. Body system outcomes were further categorised as being functional changes, or changes at macroscopic or cellular levels. The most frequently used outcomes were those detecting changes in the brain (n = 265), physical parameters measured in whole animals (n = 122) and any respiratory system changes (n = 97). Conclusions This scoping review quantifies the nature and frequency of outcomes used in preclinical studies investigating the potential impacts of nicotine administration in pregnancy on offspring. Systematic reviews of studies investigating outcomes involving animal brains, PLOS ONE | https://doi.org/10.1371/journal.pone.0280805 February 3, 2023 1 / 10 PLOS ONE Funding: This project was funded through a National Institute for Health Research (NIHR) Programme Grants for Applied Research (Programme number RP-PG-0615-20003). Tim Coleman is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this manuscript are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Nicotine exposure and offspring outcomes: A systematic scoping review and taxonomy development respiratory system, or ‘whole animal’ outcomes may have greatest potential for further advancing knowledge regarding impacts of gestational nicotine exposure on offspring. Protocol and registration Protocol for this review can be found on Open Science Framework (https://osf.io/ptmzc/). Competing interests: The authors have declared that no competing interests exist. Introduction Smoking in pregnancy causes much morbidity and mortality [1–3]. A systematic review of randomised control trials (RCTs) shows that stopping smoking in pregnancy improves birth outcomes [4]. Many countries, including the UK, recommend nicotine replacement therapy (NRT) for smoking cessation during pregnancy [5, 6] and 11% of UK pregnant smokers receive NRT prescriptions [7]. Although NRT provides nicotine without other toxic elements present in tobacco smoke, the ability for nicotine to cross the placenta and concentrate in fetal blood and amniotic fluid [8] leads to concerns that nicotine within NRT may cause fetal harm [9]. Preclinical literature could inform us of potential harms that might be due to nicotine, and many preclinical studies have investigated relationships between nicotine administered to pregnant animals and adverse outcomes [10]. However, there is no agreed core outcome set for measuring potential offspring harm from nicotine and there appears to be great diversity in outcomes used. For many preclinical study outcomes, there is no direct evidence that these are indicative of harm to humans; hence, such outcomes are probably best considered theoretically indicative of harm to infants born to pregnant women who use NRT. For example, in one study fetal brain stem injury was observed in rat offspring after gestational nicotine administration in maternal drinking water, and it was extrapolated that maternal smoking in pregnancy may cause similar issues, potentially leading to sudden infant death syndrome [11]. Other preclinical study issues which make finding’s relevance to humans difficult to ascertain include outcomes measured ‘in vitro’, in isolated parts of animals or in species which have little in common with humans [12]. Systematic reviews involve collating all studies relevant to research questions together, and through evidence synthesis can comprehensively answer important research questions[13]. For example, a recent systematic review of studies investigating NRT use by pregnant women found no evidence that NRT use during pregnancy causes fetal harm [14]. However, despite a thorough search, we have been unable to find any systematic reviews of preclinical studies investigating the impacts of nicotine exposure in pregnancy on mammalian offspring outcomes. We found a 20-year old review, but within this, search strategies were not described, so it was impossible to determine how comprehensive this was [10]. Other reviews have been narrative with selective choices of included literature [8, 15–18], and this lack of systematic preclinical literature synthesis has resulted in calls for rigorous, regularly-updated systematic reviews of preclinical (...truncated)