Dose and timing of prenatal tobacco exposure: threats to early child development
Authors: Maureen M Black, Prasanna Nair, Adam J Spanier
Journal: The Lancet Respiratory Medicine (2014)

For more than 50 years, we have known that prenatal tobacco exposure increases a child's risk of low birthweight and prematurity.1Simpson WJ A preliminary report on cigarette smoking and the incidence of prematurity.Am J Obstet Gynecol. 1957; 12: 868-869Google Scholar Recent studies have shown that in addition to negative growth and health consequences,2Burke H Leonardi-Bee J Hashim A et al.Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis.Pediatrics. 2012; 129: 735-744Crossref PubMed Scopus (495) Google Scholar prenatal nicotine exposure increases the risk of a wide range of behavioural and developmental problems, including attention deficit hyperactivity disorder,3Motlagh MG Sukhodolsky DG Landeros-Weisenberger A et al.Adverse effects of heavy prenatal maternal smoking on attentional control in children with ADHD.J Atten Disord. 2011; 15: 593-603Crossref PubMed Scopus (26) Google Scholar conduct disorders,4Gaysina D Fergusson DM Leve LD et al.Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs.JAMA Psychiatry. 2013; 70: 956-963Crossref PubMed Scopus (119) Google Scholar externalising behaviour problems,5Weissman MM Warner V Wickramaratne PJ Kandel DB Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood.J Am Acad Child Adolesc Psychiatry. 1999; 38 (889): 892Summary Full Text PDF PubMed Scopus (283) Google Scholar and adolescent tobacco use.6Buka SL Shenassa ED Niaura R Elevated risk of tobacco dependence among offspring of mothers who smoked during pregnancy: a 30-year prospective study.Am J Psychiatry. 2003; 160: 1978-1984Crossref PubMed Scopus (259) Google Scholar Although associations with cognition and language problems have been reported, they are less strong and enduring than the associations with behaviour problems.7Behnke M Smith VC Prenatal substance abuse: short- and long-term effects on the exposed fetus.Pediatrics. 2013; 131: e1009-e1024Crossref PubMed Scopus (416) Google Scholar Maternal tobacco use exposes the fetus to more than 7000 chemicals, including nicotine. Nicotine acts as a stimulant within the reward pathways and the nicotine receptors throughout the body, and is thought to cause hypoxia, to disrupt the nutrient supply, and to cause vasoconstriction of the placenta and umbilical vessels. The mechanisms linking nicotine to brain development are less clear, but might work through changes in metabolism and the neurotransmitter systems.8Bublitz MH Stroud LR Maternal smoking during pregnancy and offspring brain structure and function: review and agenda for future research.Nicotine Tob Res. 2012; 14: 388-397Crossref PubMed Scopus (70) Google Scholar These effects could vary by dose and timing of the nicotine exposure; exposure during the embryonic stage is likely to cause different effects from exposure later in pregnancy. The other chemicals in tobacco smoke might also play a part in disrupting early brain development; few have been studied individually. Sue Cooper and colleagues9Cooper S Taggar J Lewis S et al.Effect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomised, double-blind, placebo-controlled SNAP trial.Lancet Respir Med. 2014; (published online Aug 11.)http://dx.doi.org/10.1016/S2213-2600(14)70157-2Google Scholar report the effect of nicotine replacement therapy patches in 1050 pregnant smokers recruited at 12–24 weeks' gestation. Their finding that the intervention group experienced a reduction in smoking (validated by carbon monoxide concentration, salivary cotinine concentration, or both) 1 month after enrollment suggests that children in the intervention group had a varying period of lower tobacco exposure in the second-third trimester, despite no differences in smoking at delivery. The subsequent finding of higher rates of survival with no developmental impairment at 2 years of age in the intervention group suggests that the nicotine patch was not harmful and could have reduced children's prenatal tobacco exposure. However, questions arise regarding the mechanisms, including the timing and reduction in dose of tobacco are necessary to achieve a positive effect. No differences in birthweight, gestational age, or other birth outcomes were noted, suggesting that the mechanisms affecting the tobacco–growth association differ from the mechanisms guiding the tobacco–brain development association. No information is provided about the children's nutritional status at 2 years or about other environmental conditions that might affect early development. The absence of differences in rates of maternal smoking at the child's age of 2 years and the low rates of smoking cessation (<3%) indicate that more effective methods of smoking cessation during pregnancy are necessary. The finding that nicotine causes cell damage and impairs synaptic activity has led to the recommendation of caution in the dose and timing of nicotine patches during pregnancy, especially if women continue to smoke.10Slotkin TA Fetal nicotine or cocaine exposure: which one is worse?.J Pharmacol Exp Ther. 1998; 285: 931-945PubMed Google Scholar A strength of the Cooper and colleagues'9Cooper S Taggar J Lewis S et al.Effect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomised, double-blind, placebo-controlled SNAP trial.Lancet Respir Med. 2014; (published online Aug 11.)http://dx.doi.org/10.1016/S2213-2600(14)70157-2Google Scholar is the prospective assessment and the focus on child development at 2 years. Although early child development is the genesis of adult health and wellbeing, many studies of smoking cessation during pregnancy terminate at delivery with the birthweight and gestational status of the newborn. By examination of children's development beyond infancy, this Article generates a hypothesis by showing the need to address variability in the dose and timing of prenatal exposure to nicotine and other tobacco toxins. A 2014 report from the US Surgeon General11US Department of Health and Human ServicesThe Health Consequences of Smoking - 50 Years of Progress. A Report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta2014Google Scholar emphasises that prenatal nicotine exposure during fetal development adversely affects maternal and fetal health during pregnancy, with lasting adverse consequences for brain development. In view of the negative consequences of prenatal nicotine and other tobacco toxin exposure worldwide, WHO recommends that pregnant women abstain from smoking.12WHOWHO Report on the Global Tobacco Epidemic, 2009: Implementing Smoke-Free Environments. World Health Organization, Geneva2009Google Scholar The effectiveness of tobacco-control programmes varies widely across countries. Data from 15 European countries suggest that 26·2% of women smoke during pregnancy.13Smedberg J Lupattelli A Mardby AC Nordeng H Characteristics of women who continue smoking during pregnancy: a cross-sectional study of pregnant women and new mothers in 15 European countries.BMC Pregnancy Childbirth. 2014; 14: 213Crossref PubMed Scopus (131) Google Scholar In the USA, data from the National Survey on Drug Use and Health,14Substance Abuse and Mental Health Services AdministrationResults from the 2010 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville2011Google Scholar indicate that in 2009–10, tobacco use in non-pregnant women was estimated at 26·7%, compared with 16·3% in pregnant women. In adolescents aged 15–17 years, the rate of smoking was higher in pregnant women (22·7%) than in non-pregnant women (13·5%). Increases in electronic-cigarette advertising and use in the youth throughout the world are further causes for concern.15Duke JC Lee YO Kim AE et al.Exposure to electronic cigarette television advertisements among youth and young adults.Pediatrics. 2014; 134: e29-e36Crossref PubMed Scopus (239) Google Scholar Three primary research agendas are urgently needed. The first is an understanding of the mechanisms whereby smoking during pregnancy disrupts prenatal brain development and functioning; convincing evidence shows that brain disruption occurs.4Gaysina D Fergusson DM Leve LD et al.Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs.JAMA Psychiatry. 2013; 70: 956-963Crossref PubMed Scopus (119) Google Scholar, 8Bublitz MH Stroud LR Maternal smoking during pregnancy and offspring brain structure and function: review and agenda for future research.Nicotine Tob Res. 2012; 14: 388-397Crossref PubMed Scopus (70) Google Scholar, 11US Department of Health and Human ServicesThe Health Consequences of Smoking - 50 Years of Progress. A Report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta2014Google Scholar Advanced neurophysiological and neurodevelopmental methods can provide additional evidence regarding the dose and timing of the nicotine exposure, along with exposure to the other chemicals, on fetal brain development. A second agenda involves investigation of the effect of electronic cigarettes and other nicotine-containing vapour devices, and nicotine replacement patches used during pregnancy. The third agenda is the development and evaluation of effective tobacco prevention and control strategies. Smoking rates in women are increasing globally, particularly in countries with low and middle incomes where there is often intensive marketing and little attention to the negative consequences of smoking during pregnancy.16Nichter M Greaves L Bloch M et al.Tobacco use and secondhand smoke exposure during pregnancy in low- and middle-income countries: the need for social and cultural research.Acta Obstet Gynecol Scand. 2010; 89: 465-477Crossref PubMed Scopus (41) Google Scholar Incorporating issues of empowerment and the social context of women into gender-based strategies for tobacco control could be an effective strategy to reduce smoking during pregnancy13Smedberg J Lupattelli A Mardby AC Nordeng H Characteristics of women who continue smoking during pregnancy: a cross-sectional study of pregnant women and new mothers in 15 European countries.BMC Pregnancy Childbirth. 2014; 14: 213Crossref PubMed Scopus (131) Google Scholar and to promote the health, development, and wellbeing of women and children. We declare no competing interests. Effect of nicotine patches in pregnancy on infant and maternal outcomes at 2 years: follow-up from the randomised, double-blind, placebo-controlled SNAP trialInfants born to women who used NRT for smoking cessation in pregnancy were more likely to have unimpaired development. NRT had no effect on prolonged abstinence from smoking but did cause a temporary doubling of smoking cessation shortly after randomisation during pregnancy, which could explain findings. If findings are confirmed by subsequent research, this has potential implications for the management of smoking in pregnancy. Full-Text PDF Open Access