Within the Western world, nearly one-quarter of all pregnancies are associated with maternal smoking. In low- and medium-income countries, this number has been reported to be higher. Dissemination of knowledge of the deleterious effects of smoking while pregnant have resulted in many women attempting to reduce the harmful effects on their fetus by using nicotine-replacement therapies. Unfortunately, although the exposure to toxic substances may be reduced, these pregnancies are still associated with exposure to nicotine. The rise in the popularity of e-cigarettes among young individuals, which foster dependency on this drug, is expected to result in rises in pregnancies exposed to nicotine. Moreover, exposure of the fetus to the substances in cigarettes can occur even if the pregnant woman is exposed to second-hand smoking via paternal cigarette use.

The aim of this special issue was to bring together the current work of scientists interested in elucidating the postnatal consequences of prenatal exposure to nicotine, and/or to the compounds present in cigarette smoke. In doing so, it gathers, among other things, data on the outcomes of prenatal nicotine exposure that were presented at a symposium on ‘Postnatal effects of prenatal exposure to stress or prescription/recreational drugs’, which was organized by Kristi A. Kohlmeier and Morten P. Kristensen at the Institute of Drug Design and Pharmacology and sponsored by the Drug Research Academy at the University of Copenhagen on March 21, 2014.

Based on this work from animal and human studies, it is clear that exposure to cigarette and nicotine during vulnerable periods of pregnancy has tremendous negative consequences for the developing fetus that persist into adulthood. In this issue, La Merrill et al.Reference La Merrill, Cirillo, Krigbaum and Cohn ¹ present a comprehensive follow-up study of a cohort of women subjected prenatally to maternal cigarette smoking, and the authors report a higher risk of developing diabetes mellitus, independent of birth weight or body mass index, which represents a novel finding. Interestingly, their subject group comprised women born in the United States before the 1964 Surgeon General’s announcement of the harmful effects of smoking on the fetus, and therefore might represent a cohort in which underreporting of exposure was less than in cohorts born later when fear of public opinion may have censored reporting of more accurate smoking exposure. Furthermore, although the study was underpowered to reach a firm conclusion regarding the issue of paternal smoking effects, the authors caution that an association was detected, and this association should direct physician discussions with pregnant patients to include the possibility that paternal smoking could also enhance diabetes risk.

Although prenatal nicotine exposure clearly produces lasting metabolic alterations, it is not intuitively obvious what the underlying causal mechanisms may be. However, they may encompass the processes that are compromised by prenatal exposure to certain endocrine modulators such as the non-steroidal estrogen, diethylstilbestrol, discussed in the paper by Hatch et al.Reference Hatch, Troisi and Palmer ² This study indicated a slightly increased obesity risk as a sequela. Moreover, metabolic disturbances may be secondary to the known function of diethylstilbestrol as an endocrine disruptor, which include transgenerational effects on reproductive hormones as documented in the report by Wise et al.Reference Wise, Troisi and Hatch ³

Another harmful effect of smoking while pregnant is the compromised intrauterine development of the fetal respiratory system. Many studies have focused on the immediate impact of this damage by examining respiratory function in the 1st year of life. However, few studies have examined whether this damage has an impact later in life. In the study by Werhmeister et al.Reference Werhmeister, Nunes and Loret de Mola ⁴ in this issue, respiratory function in a cohort of children born to smoking mothers in 1993 in Brazil was studied during the period of adolescence. This National cohort was of interest as wheezing, which is one of the main symptoms of asthma, appears to be at the highest incidence in Brazil in adults based on self-reporting when compared with other nations. The authors found an association in these adolescents between maternal smoking and wheezing crises at the age of 15, as well as with protracted wheezing events at the age of 11 and 15 based on self-reporting as well as reporting by the mothers. This was substantiated by an elevated incidence of asthma diagnosis in individuals in this group at the age of 15. This association was the strongest when maternal smoking during pregnancy was high, exceeding 19 cigarettes a day. Interestingly, unlike in the study of diabetes risk with parental smoking, paternal smoking was not found to impart a higher risk – that is, wheezing episodes and asthma diagnosis were not affected by second-hand smoke. Although the authors were unable to evaluate postnatal smoking exposure, precluding their conclusion that the critical period occurred in utero, when taken together with the finding that paternal smoking was not associated with an increase in the incidence of wheezing or asthma, these data suggest that direct exposure in fetal life enhances the risk of poor respiratory outcomes, which persist into adolescence and likely beyond.

Among the increase in risk for many adverse diseases and disorders, individuals exposed to prenatal nicotine have an increased risk of becoming addicted to drugs of abuse later in life. This suggests that prenatal exposure to nicotine serves as a developmental teratogen, altering the normal development of the brain. Indeed, several studies support the interpretation that prenatal exposure to nicotine creates abnormalities within areas of the brain critical for assigning reward to environmental stimuli. Reports contributing to the conclusion that prenatal nicotine induces alterations in neuron functions in an area of the brain, which is critical in assigning saliency to environmental stimuli, in goal seeking and in inducing arousal focused on seeking drugs of abuse, are reviewed in the article by K.A. KohlmeierReference Kohlmeier ⁵ in this issue. Alterations induced in this reward-related nucleus are hypothesized to create a functional state in which drugs of abuse provide more pleasure, which may lead to increased addiction risk upon postnatal exposure to these substances.

Although some studies have identified specific functional aberrations induced by in utero exposure to nicotine, the alterations induced within reward brain circuitry by prenatal drug exposure are incompletely understood. In a research report in this issue, one possible neural mechanism that may alter reward assignment in the brain of an individual prenatally exposed to nicotine is examined.Reference McNair and Kohlmeier ⁶ In this study, reductions in the responsitivity of glutamate receptors in a motivation-regulating brain nucleus were detected in mice exposed to nicotine prenatally. In a separate study reported in this issue, another mechanistic change in the brain that may partly underlie an elevated addiction risk later in life following prenatal nicotine exposure is examined by Christensen et al.,Reference Christensen, Nielsen and Kohlmeier ⁷ who detected altered nicotine responses at nicotinic receptors in the same arousal and motivation-related brain region.

As the number of prenatally exposed individuals is not diminishing and, in fact, may be increasing owing to the use of the nicotine patch during pregnancy and trendiness of e-cigarette use in the young, this population, with its heightened risk for addiction, diabetes and respiratory disorders, will have to be managed. Management of those at high risk for experiencing the lifelong consequences of early-life nicotine and smoking exposure hinge on successful identification of the physiological mechanisms that are altered by this damaging prenatal exposure. Such identification will enable the possibility of reversing or better managing the conditions associated with prenatal nicotine exposure. Moreover, hopefully, a critical mass of information about the damaging effects of prenatal nicotine will reduce the numbers of exposures not only via maternal smoking but also via paternal actions. We hope the data published in this themed issue contribute toward realization of these aims.